Despite improvements in breast cancer treatment, which have resulted in a decrease in mortality, breast cancer remains the most common malignancy among women in Hong Kong, China as well as in other developed countries, and it is also a leading cause of female mortality, with more than 300 000 deaths occurring annually worldwide.1,2 Surgery is the most important locoregional treatment for breast cancer patients and it has long been influenced and dominated by the teachings of Halsted,3,4 who believed that the systemic spread of breast cancer follows an ordered pathway—namely, nodal spread happens before the systemic dissemination. Hence, his advocated surgical approach aimed at radical locoregional control to achieve complete local and axillary nodal clearance. In early 1930s, Patey4 suggested modified radical mastectomy as the appropriate therapy for T1 and T2 lesions that did not involve the pectoralis major muscle. Compared with the Halsted radical mastectomy, this approach produced less surgical trauma to local tissue and morbidity. However, treatment outcomes were not affected by this lesser degree of surgical resection, in a study using a follow-up duration of 5.5 years. Maddox et al5 showed that disease-free survival (DFS) and overall survival (OS) were not significantly different for patients undergoing modified radical mastectomy compared with those undergoing conventional radical mastectomy.
Keynes proposed an even conservative locoregional treatment for breast cancer, after performing breast conservative surgery in 1929 on a woman with T1 disease.6 The results of this treatment have since been shown to be comparable to those of the previous standard treatment i.e. modified radical mastectomy. In addition, the OS is similar to that for patients undergoing modified radical mastectomy if external radiation is added to the ipsilateral breast. Consistent results have been achieved by different centers, showing that breast conservative treatment is suitable for early T-stage breast cancer.7-13
Even though the overall survival after breast conservative treatment is compatible to that after modified radical mastectomy, there exist subsets of patients who have an increased likelihood of developing local recurrence after breast conservative therapy: young patients (younger than 40 years), those who have an extensive intraductal component (EIC) or lymphovascular permeation (LVP), and those with other strong predictive factors for local recurrence.14-25 Local recurrence carries a poor prognosis because about half of patients will have concurrent systemic metastasis at the time of presentation.20
Patients who are prone to developing local recurrence after undergoing breast conservative treatment should thus be identified and advised to undergo further surgery to reduce the risk of local recurrence and hence improve survival. In our center, patients with risk factors for local failure (presence of EIC, LVP, and close margins) will be counseled about further surgical resection and completion mastectomy. This retrospective study aimed at testing the correlation between these and other risk factors and the presence of residual disease (RD) during subsequent completion mastectomy.
The study was based on patients who received a diagnosis of malignant breast carcinoma between January 1998 and December 2002. All patients initially received breast conservative surgery (wide local excision with or without axillary dissection) and subsequent completion mastectomy within 4 months after the initial operation, in either Queen Mary Hospital or Tung Wah Hospital, Hong Kong, China. The indications for completion mastectomy were the presence of EIC, LVP, a close margin in initial operation, and various risk factors for local recurrence (young age and high tumor grading as relative indications) as identified in the literature. Patients with an involved resection margin at the first operation were excluded from the study. Postoperative adjuvant chemotherapy and hormonal therapy were given to patients according to usual indications. All patients were followed up in our clinic until January 2005. Disease recurrence was assessed according to patients' symptoms and results of regular physical examination, mammography (yearly mammography), tumor marker assays (CEA and CA 15-3), and other imaging tests as indicated clinically.
Specimens from both breast conservative surgery and completion mastectomy were examined by qualified pathologists. The tumor size was recorded as the greatest diameter microscopically. The margins of every specimens of breast conservative surgery were marked in different dimensions (medial, lateral, superior and inferior) at the time of surgery, allowing determination of margin status by pathologists. The margin status was defined as close if tumor cells were present within 2 mm of any of the resection margins, and EIC was defined as positive if the proportion of ductal carcinoma in situ (DCIS) was greater than 25% of the whole tumor in pathologic sections. Tumors were classified according to the standard Bloom and Richardson grading system,26 and the presence of estrogen receptor (ER), progesterone receptor (PR), and c-erbB-2 were assessed by immuno-histochemistry. Completion mastectomy was performed according to the indications as stated above, and all residual breast tissue was dissected from underlying pectoralis major muscle together with the muscle fascia. All the margins were marked in similar fashion as the breast conservative surgery specimens. Specimens were then formalin fixed and sent to pathologists for handling immediately. Demographic data were retrieved from patients' records. Residual disease was defined as positive if the completion mastectomy specimen contained invasive or in situ carcinoma components, whereas the determination of margin status, LVP, EIC, grading, ER, PR, c-erbB-2 and other pathologic features were the same as before.
Statistical analysis was performed with SPSS ver. 12 (SPSS Inc, Chicago, USA). The chi-square test was used to analyze the association between residual disease and the following risk factors: EIC status, LVP status, margin (<2 mm vs >2 mm), age (<40 years vs >40 years), ER status, PR status, and c-erbB-2 status. A two-tailed P value of 0.05 or less was considered to be statistically significant. Logistic regression analysis was performed to further look at the significance of different risk factors with residual disease. The DFS and OS were compared between patients who were positive for residual disease and those who were negative using Kaplan-Meier curve.
A total of 46 consecutive patients were recruited within the study period. Their mean age was 46.8 years (range, 29-83 years). Twenty-one (45.7%) of the patients had invasive ductal carcinoma; 21 patients had a mixture of DCIS and invasive ductal carcinoma; and 4 (6.7%) had other types of tumor (medullary and mucinous carcinoma). The mean tumor size was 22.1 mm (range, 8-100 mm). Residual disease was present in 21 (45.7%) patients. This subgroup most commonly had DCIS (61.9%), followed by invasive carcinoma (28.6%), and papillary carcinoma (3.4%).
Risk factors for RD
Table shows the results of the chi-square analysis of associations between residual disease and various risk factors. In all, 28 (60.9%) patients had EIC, and 17 (60.7%) EIC-positive patients had residual disease. The presence of EIC in the initial breast conservative surgery was associated with a higher risk of residual disease in subsequent completion mastectomy (P=0.011). All other factors were not significantly associated with a higher likelihood of residual disease. Presence of EIC was also shown to be the only significant risk factor in logistic regression model (P=0.010).
Within the follow-up period (mean, 52.8 months), there was no local recurrence in the ipsilateral chest wall after completion mastectomy. Five (10.9%) of the 46 patients developed distant metastasis, and 1 (2.2%) mortality was recorded after completion mastectomy and relevant adjuvant therapies (Figure).
The mean DFS was 52.04 months (range, 7-83 months) and the mean OS was 55.28 months (range, 29-83 months), which were deemed satisfactory. When the patients with residual disease were compared with those without residual disease after completion mastectomy had been performed, there was no significant difference in DFS (52.05 vs 52.04 months; P=0.999) or in OS (55.05 vs 55.48 months; P=0.929) (Figure).
Because of breast cancer screening programs for high-risk individuals, breast cancers are now usually detected and treated at an earlier stage than before; hence, more patients can benefit from breast conservative surgery. Still, the problem of local recurrence after breast conservative surgery should not be underestimated. An overall of 4% to 20% local recurrence rate was reported 10 years after breast conservative therapy, and recurrence most frequently appeared in the second and third years after completion of treatment. Local recurrence is a potential marker for poor prognosis, and Barros et al25 showed that local recurrence is associated with a rate of 51.8% (10/17) distant metastasis at the time of presentation. Therefore, prevention of relapse is of paramount importance. Detailed subgroup analyses have identified the presence of EIC, LVP, close resection margins, and young age as the strong predictive risk factors for local failure after breast conservative therapy14-24 Fourquet et al14 showed that young age (<40 years), residual malignant microcalcification, a positive margin, EIC with a positive margin, LVP, vascular invasion, and a higher proliferation rate were associated with an increased risk of local recurrence. Sinn et al showed similar results: EIC, Bloom and Richardson grade III, lobular carcinoma, LVP, and age younger than 40 years were identified as risk factors. Voogd et al18 found that relative risks for local recurrence were 2.9 for age younger than 35 years, 4.1 for high-grade EIC, and 2.5 for microscopic margin involvement with vascular invasion. Furthermore, Touboul et al19 reported a 3.15-fold increased risk of local recurrence for age younger than 40 years, and a 2.6-fold increased risk for EIC.
According to most available studies, an involved resection margin seems to be the most important factor to be associated with subsequent local failure of breast conservative therapy18. Thus, many authors have suggested that the achievement of a clear resection margin in breast conservative surgery be the principle of this type of surgery.27 In our center, for patients who have undergone breast conservative surgery with an involved margin, reexcision of the margin is performed until the return of a clear margin; then, external radiation is applied as part of the local regimen. In this study, we assessed the impact of the presence of EIC and other factors on local failure after a clear margin had been achieved. Completion mastectomy was performed according to a protocol that allowed pathologic examination of the remaining whole breast tissue to exclude residual disease in the ipsilateral breast. Residual tumor cells have a high potential to multiply and develop into subsequent local recurrence and systemic dissemination.
The term EIC was first introduced in the mid-1980s to describe a distinctive pattern of DCIS that is seen in association with a subset of invasive breast cancer. It is generally defined as the presence of a DCIS element in more than 25% of the total invasive tumor volume. Besides being a risk factor for local failure, the presence of EIC was also associated with residual disease in reexcision specimens after breast conservative surgery. Barros et al25 found that the most reliable predictor of local recurrence was margin status, and the presence of EIC predicted the likelihood of margin involvement. Smitt et al28 showed that EIC and young age were predictive of residual disease in the reexcision specimen. Holland et al29 also demonstrated this correlation between EIC and residual disease, and concluded that the presence of EIC may pose an increased subclinical tumor burden in the remainder of the breast, thereby increasing the risk of residual disease.
Although the patient sample in our study was relatively small, residual disease was commonly encountered (45.7%) in our cohort after the exclusion of patients with a positive resection margin. Residual disease represents a substantial problem for patients undergoing breast conservative surgery, because a large proportion are likely to later develop local recurrence due to residual cancer-cell clones left behind in the ipsilateral breast. Our study also showed that presence of EIC was associated with a higher risk of residual disease (60.7% (17/28) vs 39.3% (11/28); P=0.011). Although the sites of residual disease in the completion mastectomy specimens, in relation to the tumor site, were not documented in the pathologic examination, this observation is still consistent with the previous findings regarding the relation between residual disease and presence of EIC during the initial operation. Correlation with other factors—age, LVP, and ER, PR, and c-erbB-2 status—were not statistically significant in our study. Despite the high residual disease rate in our cohort, no local failure after completion mastectomy was documented after a mean follow-up duration of 52.8 months. The DFS and OS were also satisfactory. Given such satisfactory results in terms of local failure rate, DFS, and OS, we believe the presence of EIC in breast conservative surgery may justify a more aggressive surgical approach to prevent local failure, although the radical approach of completion mastectomy may deplete the potential benefit of breast conserving surgery in preserving body image and quality of life. In the consideration of psychological impacts, Curran et al showed that patients undergone BCT was similar to those received mastectomy in term of fear of subsequent relapse. In a study involving Chinese population by Yeo et al,31 similar findings were observed. Even patients undergone mastectomy were not better in term of fear of relapse than those received BCT, the risk of local failure should be balanced with the benefit of breast conservation.
The presence of LVP was shown not to be a risk factor for residual disease in our study, although it was proven to be a strong predictor of local failure after breast conservative treatment. Lymphovascular permeation is determined histologically by the presence of tumor emboli in thin-walled vascular structures, it is however difficult to distinguish these vascular channels from capillaries, venules, or lymphatic vessels. Difficulty is also encountered by pathologists in distinguishing true vascular or lymphatic channels from soft-tissue space in a histologic section. These problems account for the wide variation in the reported frequency of LVP in the literature (20%-54%). Lymphovascular channels in the underlying muscle are rarely involved, probably owing to the presence of thick muscular fascia. Because LVP is a risk factor for flap recurrence after mastectomy,32 tumor emboli causing local failure are probably present in lymphovascular channels in the skin flap rather than in the muscle or remaining breast tissue after breast conservative surgery. This scenario may explain why LVP was not a risk factor for residual disease in completion mastectomy in our study.
We found that the majority of cases of residual disease were pure DCIS (61.9%). It is still not fully known whether radiation is able to suppress or kill these clones of DCIS if they are not removed surgically. The NSABP-1733 and EORTC34 studies demonstrated the benefit of performing additional radiotherapy after lumpectomy in DCIS patients, benefits observed even in those with the low-grade, non-comedo type of DCIS in subclass analysis. Although there is level I and grade A evidence that shows that radiation to the breast after lumpectomy significantly improves local control in patients with DCIS, DCIS is never treated primarily by radiation—mostly because DCIS is relatively indolent in growth and contains a hypoxic compartment that renders it relatively radioresistant.35
It is generally accepted that surgery is the preferred primary treatment for DCIS and that radiotherapy serves as the adjuvant therapy. With an adequate resection margin, Silverstein et al36 and Moran et al37 reported that lumpectomy alone yields low local recurrence rates for the group with additional radiation. The presence of residual DCIS in ipsilateral breast tissue after breast conservative treatment warrants reexcision or a more aggressive approach by completion mastectomy. The low rates of local failure and mortality suggest that this approach should be considered seriously for patients with EIC present in breast conservative surgery.
In conclusion, patients with EIC at the time of breast conservative surgery should be advised on the option on further surgery because EIC represents a general increased tendency of cancer pathogenesis, at least on the ipsilateral breast. Although this may scarify the psychological benefit of breast conservative surgery, further surgery is still preferred to offer as an option of treatment. Or close monitoring on EIC patients is warranted after breast conservative surgery to allow early detection of local failure.
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