Abstract
Introduction: The role of ductal carcinoma in situ (DCIS) component on the outcome of invasive breast cancer is not yet completely clear. Our study aims to assess the impact of the presence and quantity of DCIS component on the outcome of patients operated for invasive breast cancer. Materials and methods: We collected retrospective data about patients operated at their breast for invasive cancer between 2007 and 2012, focusing on the presence of DCIS component. Then, we divided patients into four groups based on the quantity of DCIS component as follows: not found (group A), minimal (group B, <25%), extensive (group C, 25-75%), and prevalent (group D, >75%). We further defined “extensive intraductal component” (EIC) groups C and D together. Results: DCIS component was associated with young age, familial history of breast cancer and worse biological characteristics, including high grading, higher prevalence of Her2/Neu overexpression, hormone receptors negativity, comedo-like necrosis and multifocality/multicentricity. Despite the unfavorable prognostic factors, invasive cancers associated with EIC were frequently treated with radical surgery and resulted to have long disease-free survival and low local recurrence rate. In patients with DCIS component (groups B, C, and D) the extension of this component resulted indirectly correlated with local recurrence rate, tumor lymphovascular invasion, and lymphnode extracapsular invasion. The highest prevalence of local recurrences was found in group B, which tended to be less frequently treated with radical surgery than group D (P<0.05) and C (P=n.s.). Conclusions: Different clinical and tumor features among invasive breast cancer with and without DCIS component indicate that they are distinct entities probably originating by different pathways that deserve to be studied. Furthermore, the controversial results about the management of cancer with minimal intraductal component require further studies in order to reduce local recurrence.
Keywords: Breast cancer, ductal carcinoma in situ component, extensive intraductal component, overall survival, disease-free survival
Introduction
Ductal carcinoma in situ (DCIS) is found in a great number of pathological specimens to accompany invasive breast cancer, being sometimes very limited, while representing some other times the majority of the neoplastic lesion. Owing to this correlation and other evidences present in the literature DCIS is considered as a non-obligate precursor of invasive breast carcinoma [1]. However, in the literature are recorded also cases of invasive breast cancer without coexistence of DCIS especially among triple negative cancers [1]. Anyway, the co-existence of a DCIS component with the invasive breast cancer has always been described as a marginal aspect of invasive breast cancer, until Schnitt and colleagues introduced the definition of “extensive intraductal component” (EIC) as the presence of 25% or more intraductal neoplasia in an invasive breast carcinoma [2], and the group of Veronesi took EIC into consideration in their new breast cancer classification [3].
An abnormal mammographic finding is by far the most common presentation of DCIS, which in the most cases appears as a cluster of microcalcifications [4,5]. As a consequence, after the introduction of an organized breast cancer screening by mammography in our region, we observed a remarkable increase in the detection rate of pure DCIS (23% of non palpable breast lesions) and an increased incidence of EIC [6-9]. This increase may be explained by the greater attention that pathologists payed in intraductal component search and description. However, an alternative explanation could also be the high sensitivity of mammography for intraductal neoplasia that helps in detecting very small invasive breast cancer associated with EIC.
The role of EIC on breast cancer prognosis remains unclear, and its surgical management is still argument of debate. In fact, the presence of DCIS remains one of the principal risk factors for breast demolition, due to its usual multifocality and multicentricity [10-13], and its frequent correlation with margin infiltration in case of breast conservative surgery (BCS) [14,15], so that there is still disagreement when considering what constitutes an adequate margin of excision in DCIS. In addiction, EIC has been demonstrated to be an independent risk factor for local recurrence after BCS especially in young, premenopausal women [16,17], and for residual disease in completion mastectomies after BCS [18]. Moreover, the incidence of nipple involvement in DCIS has become always more relevant with the increasing interest in nipple-sparing mastectomies [19].
Although DCIS is well recognized to be a possible precursor of invasive ductal carcinoma [20,21], the proportion of women with mammographically detected DCIS in whom invasive carcinoma will develop within their lifetimes is uncertain, as well as the proportion of biologically indolent DCIS which is unlikely to become clinically significant. And the literature is lacking about the role of intraductal component by the presence of an invasive breast cancer. Then, our study aims to assess the impact of the presence and quantity of intraductal component on the outcome of patients operated for invasive breast cancer.
Materials and methods
We retrospectively analyzed data form our registry about all women operated at their breast for invasive breast cancer in our Clinic between January 2007 and December 2012. This retrospective chart review study was designed according to the Declaration of Helsinki and it was approved by the Internal Review Board (IRB). Moreover, this study regarding consent for processing data used in this retrospective analysis follows the dictates of the general authorization to process personal data for scientific research purposes by the Italian Data Protection Authority (Authorization no. 9/2013). In the present study we included only cases of invasive breast cancer where the DCIS component extension was mentioned. The study population was divided into four groups in accordance with DCIS component quantity, as follows: group A) DCIS not found in standard slides; group B) minimal DCIS extension (<25% of the neoplastic lesion), group C) extensive (25-75%), and group D) prevalent (>75%). We further defined “extensive intraductal component” (EIC) groups C and D together. Pathological specimens were routinely assessed as suggested by the European guidelines [22]. Samples approximately 30 mm or less in maximum diameter were completely sliced, embedded and examined histologically while for larger specimens sampling was done according to the European guidelines [22].
Clinical and histological information
Collected data included the following clinical and pathological factors. Patient characteristics: age at diagnosis, body mass index (BMI), familial history of breast cancer, fertility status, and eventual use of therapies containing estrogens. Tumor characteristics were considered as follows: histological type, TNM classification (VII ed. AJCC/UICC, 2009), tumor grading, Mib1/Ki-67 proliferation index, hormone receptors status including estrogen receptor (ER), progesteron receptor (PR) and HER2/neu expression, and other microscopic features evaluated in the new classification proposed by the group of Veronesi such as multifocality/multicentricity, peritumoral vascular invasion (PVI), peritumoral inflammation, lymph node extracapsular invasion or bunched axillary lymph nodes [3].
Tumor histology was classified according to the World Health Organization criteria [23,24] and tumor grade was evaluated following the recommendations of Elston and Ellis [25]. Multifocality/multicentricity, PVI, peritumoral inflammation, lymph node status was defined as previously described [26,27]. The expression of ER, PR, and Her-2/Neu were evaluated by immunohistochemistry. We considered ER or PR receptor positivity as positive in any nuclear staining ≥1%. We considered Her-2/Neu overexpressed when staining resulted 3+ or 2+ with FISH amplification, negative if value was 0, 1+ or 2+ without FISH amplification. The following subtypes of breast cancer were considered in this study as previously defined: luminal A, luminal B, luminal Her, Her2-enriched, and triple-negative [26]. Moreover, the therapeutic management was investigated, including conservative versus radical, breast and axillary surgery, eventual neoadjuvant or adjuvant therapies.
Statistical analysis
Data was analyzed using R (version 3.0.1) and considering significant P<0.05. Data was presented where appropriate as mean (± standard deviation), median and interquartile range (IQR), proportions, or hazard ratio (HR) with relative 95% confidence interval. Univariate analysis was performed by t-test or Wilcoxon test in case of continuous variables, chi-square test or Fisher exact test in case of categorical variables. Overall survival (OS), disease-free survival (DFS), and loco-regional recurrences were also considered. Therefore, Kaplan-Meyer curves or cumulative events curves were drown to compare OS, DFS, and loco-regional recurrences among the four groups. Furthermore, Log-rank test, univariate, and multivariate Cox proportional hazards regression model analysis were performed.
Results
Patient characteristics and treatment
We analyzed data about 1013 women affected by invasive breast cancer with a mean age at diagnosis of 58.91 years (±12.35) and a median follow up of 49 months (30-69). In 580 cases the DCIS component was not found (group A), in 197 cases was minimal (group B), in 191 cases was extensive (group C), and in 45 cases was prevalent (group D). In Table 1 we show the characteristics of the population subdivided by DCIS component extension. In the case of extensive DCIS component (group C) the age at intervention was significantly lower than in group A where DCIS component was not found (P<0.05). A high extent of DCIS component (group C or groups C and D together) was significantly associated to an increased prevalence of familial history of breast cancer than group A or B (P<0.05). In group C and D we had the lowest prevalence of BCS as first line surgical treatment and as definitive treatment (Table 1). The prevalence of other treatment options is described in Table 1 and, as expected, adjuvant treatments presented lower prevalence among the groups managed with higher rates of radical surgery.
Table 1.
Characteristics of the population subdivided by intraductal component extension
| Not found (A) | Minimal (B) | Extended (C) | Prevalent (D) | ||
|---|---|---|---|---|---|
| Age (years) | 59.81 (±12.51) | 58.42 (±12.07) | 56.9 (±12.01) | 58.04 (±12.22) | (2) |
| Age <50 years | 23.6% (137/580) | 28.4% (56/197) | 31.4% (60/191) | 31.1% (14/45) | (2) |
| BMI (kg/m2) | 25.88 (±5.25) | 25.96 (±5.47) | 25.89 (±4.77) | 25.46 (±4.77) | ns |
| Tobacco smoke | 4.3% (21/487) | 8.6% (12/139) | 6.2% (10/160) | 2.6% (1/39) | (1) |
| Familial history of breast cancer | 35.6% (64/180) | 32.6% (30/92) | 53.8% (35/65) | 53.8% (7/13) | (2, 4) |
| Use of OC | 39.5% (32/81) | 46.4% (13/28) | 48.5% (16/33) | 0% (0/9) | (3, 5, 6) |
| Post-menopausal status | 81.2% (471/580) | 76.6% (151/197) | 69.6% (133/191) | 73.3% (33/45) | (2) |
| First breast surgical treatment | |||||
| BCS | 63.4% (368/580) | 62.4% (123/197) | 52.9% (101/191) | 44.4% (20/45) | (2, 3, 5) |
| Mastectomy | 36.6% (212/580) | 37.6% (74/197) | 47.1% (90/191) | 55.6% (25/45) | (2, 3, 5) |
| Axilla surgical treatment | |||||
| CALND | 41.9% (243/580) | 46.7% (92/197) | 43.5% (83/191) | 31.1% (14/45) | ns |
| SLNB | 55.2% (320/580) | 51.3% (101/197) | 55.5% (106/191) | 64.4% (29/45) | ns |
| None | 2.9% (17/580) | 2% (4/197) | 1% (2/191) | 4.4% (2/45) | ns |
| Second breast surgical treatment | |||||
| Nothing | 82.1% (302/368) | 78.9% (97/123) | 61.4% (62/101) | 50% (10/20) | (2, 3, 4, 5) |
| BCS | 8.2% (30/368) | 9.8% (12/123) | 16.8% (17/101) | 15% (3/20) | (2) |
| Mastectomy | 9.8% (36/368) | 11.4% (14/123) | 21.8% (22/101) | 35% (7/20) | (2, 3, 4, 5) |
| Mastectomy as definitive treatment | 42.8% (248/580) | 44.7% (88/197) | 58.6% (112/191) | 71.1% (32/45) | (2, 3, 4, 5) |
| Other treatments | |||||
| Neoadjuvant | 5.5% (32/580) | 2% (4/197) | 3.1% (6/191) | 6.7% (3/45) | (1) |
| Adjuvant radiotherapy | 61.1% (350/573) | 60.2% (118/196) | 50.5% (94/186) | 27.3% (12/44) | (2, 3, 5) |
| Adjuvant chemotherapy | 39.3% (225/573) | 47.4% (93/196) | 47.3% (88/186) | 18.2% (8/44) | (1, 3, 5) |
| Adjuvant hormonaltherapy | 79.2% (454/573) | 81.6% (160/196) | 82.8% (154/186) | 54.5% (24/44) | (3, 5) |
Significant differences between: 1) Absent vs. Minimal; 2) Absent vs. Extended; 3) Absent vs. Prevalent; 4) Minimal vs. Extended; 5) Minimal vs. Prevalent; 6) Extended vs. Prevalent. (ns) = non significant.
Tumor characteristics and staging
Considering the whole population, the majority of cancers were ductal invasive carcinomas and this prevalence was significantly higher in group B or C than group A (P<0.05) (Table 2). As a consequence, the prevalence of invasive lobular carcinoma in group A was significantly higher than in group B, C, or D (P<0.05) (Table 2). In group D we found the significantly lowest prevalence of ER positivity (P<0.05) (Table 2). Furthermore, in groups C and D we found a high prevalence of luminal Her-2 and Her-2 enriched (Table 2). In addition, basal-like subtype was more common in group A than group C (P<0.05). Comedo-like necrosis presented a direct correlation with the amount of DCIS component extension and was significantly lower in group A than B, C, or D (P<0.05) (Table 2). Tumor multifocality/multicentricity was higher in group C and D than group A (Table 2). Moreover, among groups B, C, and D PVI was indirectly correlated with DCIS component extension as well as extracapsular invasion of lymph node metastasis (Table 2).
Table 2.
Tumor characteristics subdivided by intraductal component extension
| Not found (A) | Minimal (B) | Extended (C) | Prevalent (D) | ||
|---|---|---|---|---|---|
| Histological type | |||||
| Ductal invasive carcinoma | 79.8% (463/580) | 88.3% (174/197) | 89.0% (170/191) | 88.9% (40/45) | (1, 2) |
| Lobular invasive carcinoma | 12.2% (71/580) | 4.6% (9/197) | 5.2% (10/191) | 2.2% (1/45) | (1, 2, 3) |
| Ductal and lobular invasive carcinoma | 4.0% (23/580) | 5.1% (10/197) | 3.7% (7/191) | 2.2% (1/45) | ns |
| Other invasive carcinoma | 4.0% (23/580) | 2% (4/197) | 2.1% (4/191) | 6.7% (3/45) | ns |
| Tumor characteristics | |||||
| ER positivity | 85.3% (481/564) | 87.7% (171/195) | 85.8% (163/190) | 63.6% (28/44) | (3, 5, 6) |
| PgR positivity | 70.7% (399/564) | 69.7% (136/195) | 71.1% (135/190) | 54.5% (24/44) | (3, 6) |
| Ki-67/Mib-1 >20 | 30.4% (165/543) | 37.5% (72/192) | 32.8% (60/183) | 25% (4/16) | ns |
| Molecular Subtype | |||||
| Luminal A | 55.5% (302/544) | 48.4% (92/190) | 48.9% (89/182) | 27.8% (5/18) | (3) |
| Luminal B | 24.6% (134/544) | 31.1% (59/190) | 28% (51/182) | 11.1% (2/18) | ns |
| Luminal Her2 | 5.3% (29/544) | 7.9% (15/190) | 8.8% (16/182) | 22.2% (4/18) | (3) |
| Her2 enriched | 3.1% (17/544) | 5.3% (10/190) | 8.8% (16/182) | 22.2% (4/18) | (2, 3, 5) |
| Basal-like | 11.4% (62/544) | 7.4% (14/190) | 5.5% (10/182) | 16.7% (3/18) | (2) |
| Comedo-like necrosis | 0.5% (3/580) | 17.3% (34/197) | 27.7% (53/191) | 40% (18/45) | (1, 2, 3, 4, 5) |
| Multifocality /multicentricity | 13.6% (79/580) | 17.3% (34/197) | 25.1% (48/191) | 24.4% (11/45) | (2, 3) |
| PVI | 21.4% (124/580) | 37.1% (73/197) | 31.4% (60/191) | 4.4% (2/45) | (1, 2, 3, 5, 6) |
| Peritunoral inflammation | 0.9% (5/580) | 0% (0/197) | 1.6% (3/191) | 0% (0/45) | ns |
| Lymph nodes characteristics | |||||
| Isolated tumor cells | 1.7% (10/580) | 0.5% (1/197) | 1% (2/191) | 2.2% (1/45) | ns |
| Micrometastases | 5.2% (30/580) | 6.1% (12/197) | 3.7% (7/191) | 6.7% (3/45) | ns |
| Extracapsular invasion of lymph node metastasis | 8.8% (51/580) | 14.2% (28/197) | 11.5% (22/191) | 0% (0/45) | (1, 3, 5, 6) |
| Bunched axillary lymph nodes | 2.8% (16/580) | 3% (6/197) | 1% (2/191) | 0% (0/45) | ns |
Significant differences between: 1) Absent vs. Minimal; 2) Absent vs. Extended; 3) Absent vs. Prevalent; 4) Minimal vs. Extended; 5) Minimal vs. Prevalent; 6) Extended vs. Prevalent. (ns) = non significant.
In Table 3 we show the TNM staging of the tumor among the studied groups. We found in group D a higher prevalence of T1mic cancers and lower prevalence of T1 and T2 tumors than in the other groups (P<0.05) (Table 3). Group D showed the highest prevalence of N0 and TNM stage I, and when present, axillary nodal involvement was always micrometastatic. In addition, group D had a significant higher prevalence of G3 grading than groups A, B, or C. (P<0.05) (Table 3).
Table 3.
Tumor stage subdivided by intraductal component extension
| Not found (A) | Minimal (B) | Extended (C) | Prevalent (D) | ||
|---|---|---|---|---|---|
| Tumor size | |||||
| T1m | 0% (0/580) | 0% (0/197) | 0% (0/191) | 93.3% (42/45) | (3, 5, 6) |
| T1 | 73.1% (424/580) | 76.1% (150/197) | 75.9% (145/191) | 6.7% (3/45) | (3, 5, 6) |
| T2 | 21.4% (124/580) | 19.8% (39/197) | 23% (44/191) | 0% (0/45) | (3, 5, 6) |
| T3 | 4.1% (24/580) | 2.5% (5/197) | 1% (2/191) | 0% (0/45) | (2) |
| T4 | 1.4% (8/580) | 1.5% (3/197) | 0% (0/191) | 0% (0/45) | ns |
| N | |||||
| N0 | 69.3% (402/580) | 59.4% (117/197) | 67% (128/191) | 93.3% (42/45) | (1, 3, 5, 6) |
| N1 | 20.3% (118/580) | 25.9% (51/197) | 19.9% (38/191) | 6.7% (3/45) | (3, 5, 6) |
| N2 | 5.2% (30/580) | 9.6% (19/197) | 9.9% (19/191) | 0% (0/45) | (1, 2, 5, 6) |
| N3 | 5.2% (30/580) | 5.1% (10/197) | 3.1% (6/191) | 0% (0/45) | ns |
| TNM stage | |||||
| I | 56.2% (326/580) | 52.8% (104/197) | 54.5% (104/191) | 91.1% (41/45) | (3, 5, 6) |
| II | 29.5% (171/580) | 31% (61/197) | 30.9% (59/191) | 6.7% (3/45) | (3, 5, 6) |
| III | 12.4% (72/580) | 13.7% (27/197) | 13.1% (25/191) | 0% (0/45) | (3, 5, 6) |
| IV | 1.9% (11/580) | 2.5% (5/197) | 1.6% (3/191) | 2.2% (1/45) | ns |
| Grading | |||||
| G1 | 23.1% (134/580) | 24.4% (48/197) | 20.4% (39/191) | 6.7% (3/45) | (3, 5, 6) |
| G2 | 55% (319/580) | 49.2% (97/197) | 50.8% (97/191) | 44.4% (20/45) | ns |
| G3 | 21.9% (127/580) | 26.4% (52/197) | 28.8% (55/191) | 48.9% (22/45) | (3, 5, 6) |
Significant differences between: 1) Absent vs. Minimal; 2) Absent vs. Extended; 3) Absent vs. Prevalent; 4) Minimal vs. Extended; 5) Minimal vs. Prevalent; 6) Extended vs. Prevalent. (ns) = non significant.
Overall and disease-free survival
In Figure 1A we show the overall survival among the studied groups, and it is possible to notice the higher survival rates of group D, even if the differences do not reach statistically significance. In Figure 1B we show the disease-free survival and the only difference closed to significance was between group B and group D (P=0.074). We further analyzed by univariate and multivariate Cox proportional hazards regression model the factors influencing disease-free survival. In Table 4 we found a decreasing disease-free survival associated to a decrease of DCIS component extension. In particular, we found that, after multivariate correction, group B had a significant lower disease-free survival than group D (HR 5.61; 95% C.I. 1.06-29.62) (P<0.05) (Table 4). In addition, group B had a non-significant lower disease-free survival than group C (HR 1.33; 95% C.I. 0.56-3.18) (P=0.518). In Figure 1C we found a non-significant high prevalence of local recurrences in group B than groups C and D.
Figure 1.
Kaplan-Meier and cumulative event curves: A: Overall-survival among studied groups; B: Disease-free survival among the studied groups; and C: Local recurrences among the studied groups.
Table 4.
Univariate and multivariate Cox proportional hazards regression model analysis
| Intraductal component | HR (95% CI) | P | HR (95% CI)* | P |
|---|---|---|---|---|
| Group D (prevalent) | Reference | 1.000 | Reference | 1.000 |
| Group C (extended) | 3.34 (0.72-15.43) | 0.122 | 4.21 (0.83-21.25) | 0.082 |
| Group B (minimal) | 3.80 (0.81-17.87) | 0.091 | 5.61 (1.06-29.62) | <0.05 |
| Group A (Not found) | 2.38 (0.55-10.25) | 0.245 | 2.93 (0.59-14.5) | 0.187 |
Multivariate analysis with correction for: TNM stage, grading, definitive surgery, comedo-like necrosis and tumor molecular Subtype.
Discussion
From this study emerged an association of EIC (groups C and D) with luminal Her, Her-enriched, comedo-like necrosis, multifocality/multicentricity, high tumor grading, younger age, and familial history of breast cancer. Tumor PVI and extracapsular invasion of lymph node metastasis were more prevalent in patients with DCIS component (groups B and C) than in group A, and the amount of DCIS component resulted indirectly correlated with local recurrence rate, tumor PVI, and extracapsular invasion of lymph node metastasis. Group A had a higher prevalence of basal-like tumor subtype than group C. In addition, Cancers with prevalent DCIS component (group D) were mainly constituted by pT1mic tumors, and showed the highest survival rate, even without reaching statistical significance. On the other hand, the highest prevalence of local recurrences was found in case of minimal DCIS component (group B), which tended to be less frequently treated with radical surgery than groups D and C.
EIC is well recognized to be a risk factor for local recurrences in case of BCS [16], and some authors suggest to consider the proliferation activity of cancer cells in the DCIS component as one of the most important predictive factors of local recurrence in case of invasive breast cancer [17]. Our data show a significant correlation of DCIS component presence with many bad prognostic factors, which may also explain its strong recurrence trend.
For what concerns patients age, many studies demonstrated a correlation of EIC with young age and premenopausal status [14,16,17,28-30], both conditions in which the DCIS component seems to have an intrinsically higher recurrence potential than in older patients [31]. In our population, if compared with cancers without an evident DCIS component, patients with EIC resulted to be significantly younger and to more frequently report familial history of breast cancer. Although in the literature BRCA genes mutations correlate with a lower prevalence of DCIS component than cancers not associated with mutations (59% vs 76%, p n.s.) [32], we can support our result with the recognized higher prevalence of familial history of breast cancer in young, premenopausal women [33].
Also the grade of concomitant DCIS [34], its multifocality/multicentricity [10-13], and the presence of eventual comedo-like necrosis [35] have been demonstrated to be predictive of an aggressive biological behavior and consequently of an unfavorable prognosis in patients with invasive breast carcinoma. And our data confirmed a significant correlation of DCIS component presence with high grade tumors, multifocality/multicentircity, and comedo-like necrosis.
Taking into consideration molecular subtypes, the literature has widely demonstrated that cancers which overexpress Her2/neu have the worst prognoses among invasive breast carcinomas, but there is very few data about molecular subtypes within the DCIS component of invasive cancers, because Her2/neu quantification does not currently represent a standard examination in case of DCIS. However, in our population we observed an increased prevalence of luminal Her-2, and Her-2-enriched subtypes among invasive breast cancers with DCIS component. These findings are in accordance with that recently published by Zhang et al. [36].
Despite the correlation of EIC with all this unfavorable prognostic factors, both in the literature and in our study population, our data showed EIC (groups C and D) to have a high overall survival rate and a low local recurrence rate. These encouraging results may be clearly explained by the high prevalence of definitive radical surgery in patient with EIC, probably due to the actual knowledge of EIC association with high recurrence rates after breast conservation. In contrast, in group B with minimal DCIS component, BCS had prevalence similar to group A and a DFS significantly lower than group D despite the adjustment for TNM stage. This could be also explained by the lower prevalence of definitive radical treatment in group B than group D or C.
In the literature it is found that breast cancer is a heterogeneous and complex disease, embracing several entities that have different histological features, risk factors, and clinical behavior [37]. Furthermore, it is though that in situ cancer is the precursor of all these heterogeneous invasive breast cancers. However, is situ breast cancer lacks a major feature that characterizes other cancers (eg cervix cancer); the fact that it has never been demonstrated that removal of the DCIS lesion reduces the subsequent incidence of invasive breast cancers [38]. From our study emerged that group A (no evidence of DCIS component) had different tumor characteristics than other groups with DCIS component. Also Zhang et al. found that microinvasive breast cancer associated with DCIS component and invasive breast cancer had different characteristics [36]. This suggests us to study the possible existence of a group of invasive breast cancers which could result from a direct transformation of ductal or lobular cells, and not originating from a pre-existing in situ neoplasia. In this perspective, considering only the group originating from a pre-existing in situ neoplasia the small invasive cancers with an abundant DCIS component (group D) may represent an initial stage of neoplastic infiltration process, while those with a minimal DCIS component (group B) may be the expression of an advanced stage of invasiveness. In fact, DCIS component amount resulted indirectly correlated with some histological characteristics of biological aggressiveness and advanced invasiveness, such as tumor PVI and extracapsular invasion of lymph node metastasis [39-41].
This interesting hypothesis about two possible origins of invasive breast carcinoma may also explain the paradoxical higher local recurrence rate among patients with minimal intraductal component (group B), which are more frequently submitted to BCS despite their probable association with worse prognostic factors. Finally, our study lays the foundation for a further question to be developed in future research. In fact, an increased prevalence of local recurrences seems to be associated not only with EIC, but also with all those tumors (including group B) that have a minimal DCIS component, whose characterization and surgical management should be explored in the future.
The main limitation of the present study was the retrospective nature of this chart review analysis. In fact, the quantification of the in situ tumor component is not easy to define by the standard histological methods. First, because wide tumor samples are usually not completely analyzed by routinely methods allowing the possibility to miss the presence of the in situ tumor component. Second, because in situ tumor component could extend beyond the excised tumor lesion and could also be missed by pre-operative breast imaging work-up. In fact, in situ breast cancer is considered the precursor of the majority of invasive breast cancers while in this study we had a quite high proportion of samples in group A (without an in situ component) than in groups B, C, and D. However, in group A according to the literature we had a relative high prevalence of basal-like tumor subtype [1]. Furthermore, the prevalence of DCIS component and its groups of extension (groups B, C, and D) among our 1013 patients resulted comparable to that of a previous study on 250 women published by Elling and colleagues [14]. In particular, in our population a DCIS component was present in the 42.74% of cases, resulting minimal, extensive and prevalent respectively in the 19.45%, 18.85%, and 4.44%, while Elling and colleagues described a prevalence of in situ component of 50.8%, with a selective prevalence of minimal, extensive and predominant DICS respectively in the 14.0%, 31.2%, and 5.6% [14]. Another limitation of the present study is the limited follow up time with a median of 49 months. Anyway, in a previous study we found that the majority of recurrences were between 3 and 6 years [39] and in the present study more than 70% of the population had a follow up time longer than 3 years.
In summary, the presence of different clinical and tumor features between invasive breast cancer with and without DCIS component indicate that they are distinct entities probably originating from different pathways that deserve to be studied. In fact, our data suggested that invasive breast cancers with DCIS component probably originate from per-existing in situ neoplasia in young women with a family history of breast cancer, with biological characteristics of aggressiveness and high prevalence of local recurrence. Furthermore, in this study was found high disease recurrence in invasive breast cancer with minimal DCIS component that requires further studies in order to improve our knowledge and management.
Disclosure of conflict of interest
None.
References
- 1.Thike AA, Iqbal J, Cheok PY, Tse GM, Tan PH. Ductal carcinoma in situ associated with triple negative invasive breast cancer: evidence for a precursor-product relationship. J Clin Pathol. 2013;66:665–670. doi: 10.1136/jclinpath-2012-201428. [DOI] [PubMed] [Google Scholar]
- 2.Schnitt SJ, Connolly JL, Harris JR, Hellman S, Cohen RB. Pathologic predictors of early local recurrence in Stage I and II breast cancer treated by primary radiation therapy. Cancer. 1984;53:1049–1057. doi: 10.1002/1097-0142(19840301)53:5<1049::aid-cncr2820530506>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
- 3.Arnone P, Zurrida S, Viale G, Dellapasqua S, Montagna E, Arnaboldi P, Intra M, Veronesi U. The TNM classification of breast cancer: need for change. Updates Surg. 2010;62:75–81. doi: 10.1007/s13304-010-0014-y. [DOI] [PubMed] [Google Scholar]
- 4.Kang DK, Jeon GS, Yim H, Jung YS. Diagnosis of the intraductal component of invasive breast cancer: assessment with mammography and sonography. J Ultrasound Med. 2007;26:1587–1600. doi: 10.7863/jum.2007.26.11.1587. [DOI] [PubMed] [Google Scholar]
- 5.Ikeda DM, Andersson I. Ductal carcinoma in situ: atypical mammographic appearances. Radiology. 1989;172:661–666. doi: 10.1148/radiology.172.3.2549563. [DOI] [PubMed] [Google Scholar]
- 6.Driul L, Bernardi S, Bertozzi S, Schiavon M, Londero AP, Petri R. New surgical trends in breast cancer treatment: conservative interventions and oncoplastic breast surgery. Minerva Ginecol. 2013;65:289–296. [PubMed] [Google Scholar]
- 7.Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, Mariotto A, Feuer E, Edwards B. SEER Cancer Statistics Review, 1975-2004. Bethesda, MD: National Cancer Institute; 2007. Available at: seer cancer gov/csr/1975-2001. 2007. [Google Scholar]
- 8.Bernardi S, Bertozzi S, Londero AP, Gentile G, Giacomuzzi F, Carbone A. Incidence and Risk Factors of the Intraoperative Localization Failure of Nonpalpable Breast Lesions by Radio-guided Occult Lesion Localization: A Retrospective Analysis of 579 Cases. World J Surg. 2012;36:1915–1921. doi: 10.1007/s00268-012-1577-1. [DOI] [PubMed] [Google Scholar]
- 9.Cedolini C, Bertozzi S, Londero AP, Bernardi S, Seriau L, Concina S, Cattin F, Risaliti A. Type of breast cancer diagnosis, screening, and survival. Clin Breast Cancer. 2014;14:235–240. doi: 10.1016/j.clbc.2014.02.004. [DOI] [PubMed] [Google Scholar]
- 10.Lagios MD, Westdahl PR, Margolin FR, Rose MR. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer. 1982;50:1309–1314. doi: 10.1002/1097-0142(19821001)50:7<1309::aid-cncr2820500716>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
- 11.Schwartz GF, Patchefsky AS, Finklestein SD, Sohn SH, Prestipino A, Feig SA, Singer JS. Nonpalpable in situ ductal carcinoma of the breast. Predictors of multicentricity and microinvasion and implications for treatment. Arch Surg. 1989;124:29–32. doi: 10.1001/archsurg.1989.01410010035007. [DOI] [PubMed] [Google Scholar]
- 12.Bellamy CO, McDonald C, Salter DM, Chetty U, Anderson TJ. Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Hum Pathol. 1993;24:16–23. doi: 10.1016/0046-8177(93)90057-n. [DOI] [PubMed] [Google Scholar]
- 13.Patchefsky AS, Schwartz GF, Finkelstein SD, Prestipino A, Sohn SE, Singer JS, Feig SA. Heterogeneity of intraductal carcinoma of the breast. Cancer. 1989;63:731–741. doi: 10.1002/1097-0142(19890215)63:4<731::aid-cncr2820630422>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
- 14.Elling D, Vesper AS, Fiedler B, Martin H, Krocker J. Intraductal component in invasive breast cancer: analysis of 250 resected surgical specimens. Breast. 2001;10:405–410. doi: 10.1054/brst.2001.0289. [DOI] [PubMed] [Google Scholar]
- 15.Bernardi S, Bertozzi S, Londero AP, Gentile G, Angione V, Petri R. Influence of surgical margins on the outcome of breast cancer patients: a retrospective analysis. World J Surg. 2014;38:2279–2287. doi: 10.1007/s00268-014-2596-x. [DOI] [PubMed] [Google Scholar]
- 16.Jacquemier J, Kurtz JM, Amalric R, Brandone H, Ayme Y, Spitalier JM. An assessment of extensive intraductal component as a risk factor for local recurrence after breast-conserving therapy. Br J Cancer. 1990;61:873–876. doi: 10.1038/bjc.1990.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Imamura H, Haga S, Shimizu T, Watanabe O, Kinoshita J, Nagumo H, Kajiwara T, Aiba M. Relationship between the morphological and biological characteristics of intraductal components accompanying invasive ductal breast carcinoma and patient age. Breast Cancer Res Treat. 2000;62:177–184. doi: 10.1023/a:1006462328544. [DOI] [PubMed] [Google Scholar]
- 18.Yiu CC, Loo WT, Lam CK, Chow LW. Presence of extensive intraductal component in patients undergoing breast conservative surgery predicts presence of residual disease in subsequent completion mastectomy. Chin Med J (Engl) 2009;122:900–905. [PubMed] [Google Scholar]
- 19.van Dongen JA, Fentiman IS, Harris JR, Holland R, Peterse JL, Salvadori B, Stewart HJ. In-situ breast cancer: the EORTC consensus meeting. Lancet. 1989;2:25–27. doi: 10.1016/s0140-6736(89)90263-8. [DOI] [PubMed] [Google Scholar]
- 20.Liao S, Desouki MM, Gaile DP, Shepherd L, Nowak NJ, Conroy J, Barry WT, Geradts J. Differential copy number aberrations in novel candidate genes associated with progression from in situ to invasive ductal carcinoma of the breast. Genes Chromosomes Cancer. 2012;51:1067–1078. doi: 10.1002/gcc.21991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kurbel S. In search of triple-negative DCIS: tumor-type dependent model of breast cancer progression from DCIS to the invasive cancer. Tumour Biol. 2013;34:1–7. doi: 10.1007/s13277-012-0602-1. [DOI] [PubMed] [Google Scholar]
- 22.Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Luxembourg: Office for Official Publications of the European Communities; 2006. [DOI] [PubMed] [Google Scholar]
- 23.The world Health Organization Histological Typing of Breast Tumors--Second Edition. The World Organization. Am J Clin Pathol. 1982;78:806–816. doi: 10.1093/ajcp/78.6.806. [DOI] [PubMed] [Google Scholar]
- 24.Rosen P, Oberman H. 3rd series. Washinton, DC: AFIP; 1993. Tumors of the mammary gland: atlas of tumor pathology. [Google Scholar]
- 25.Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–410. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
- 26.Bernardi S, Bertozzi S, Londero AP, Angione V, Petri R, Giacomuzzi F. Prevalence and risk factors of intraoperative identification failure of sentinel lymph nodes in patients affected by breast cancer. Nucl Med Commun. 2013;34:664–673. doi: 10.1097/MNM.0b013e328361cd84. [DOI] [PubMed] [Google Scholar]
- 27.Cedolini C, Bertozzi S, Seriau L, Londero AP, Concina S, Cattin F, Geatti O, Di Loreto C, Risaliti A. Eight-year experience with the intraoperative frozen section examination of sentinel lymph node biopsy for breast cancer in a North-Italian university center. Int J Clin Exp Pathol. 2014;7:364–371. [PMC free article] [PubMed] [Google Scholar]
- 28.Recht A, Connolly JL, Schnitt SJ, Silver B, Rose MA, Love S, Harris JR. The effect of young age on tumor recurrence in the treated breast after conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 1988;14:3–10. doi: 10.1016/0360-3016(88)90043-0. [DOI] [PubMed] [Google Scholar]
- 29.Kurtz JM, Jacquemier J, Amalric R, Brandone H, Ayme Y, Hans D, Bressac C, Roth J, Spitalier JM. Risk factors for breast recurrence in premenopausal and postmenopausal patients with ductal cancers treated by conservation therapy. Cancer. 1990;65:1867–1878. doi: 10.1002/1097-0142(19900415)65:8<1867::aid-cncr2820650833>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- 30.Kurtz JM, Jacquemier J, Amalric R, Brandone H, Ayme Y, Hans D, Bressac C, Spitalier JM. Why are local recurrences after breast-conserving therapy more frequent in younger patients? J. Clin. Oncol. 1990;8:591–598. doi: 10.1200/JCO.1990.8.4.591. [DOI] [PubMed] [Google Scholar]
- 31.Dewar JA, Arriagada R, Benhamou S, Benhamou E, Bretel JJ, Pellae-Cosset B, Marin JL, Petit JY, Contesso G, Sarrazin D. Local relapse and contralateral tumor rates in patients with breast cancer treated with conservative surgery and radiotherapy (Institut Gustave Roussy 1970-1982). IGR Breast Cancer Group. Cancer. 1995;76:2260–2265. doi: 10.1002/1097-0142(19951201)76:11<2260::aid-cncr2820761113>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
- 32.Robson M, Rajan P, Rosen PP, Gilewski T, Hirschaut Y, Pressman P, Haas B, Norton L, Offit K. BRCA-associated breast cancer: absence of a characteristic immunophenotype. Cancer Res. 1998;58:1839–1842. [PubMed] [Google Scholar]
- 33.Tazzite A, Jouhadi H, Saiss K, Benider A, Nadifi S. Relationship between family history of breast cancer and clinicopathological features in moroccan patients. Ethiop J Health Sci. 2013;23:150–157. [PMC free article] [PubMed] [Google Scholar]
- 34.Kim JY, Han W, Moon HG, Park IA, Ahn SK, Kim J, Lee JW, Kim T, Kim MK, Noh DY. Grade of ductal carcinoma in situ accompanying infiltrating ductal carcinoma as an independent prognostic factor. Clin Breast Cancer. 2013;13:385–391. doi: 10.1016/j.clbc.2013.04.005. [DOI] [PubMed] [Google Scholar]
- 35.Yagata H, Harigaya K, Suzuki M, Nagashima T, Hashimoto H, Ishii G, Miyazaki M, Nakajima N, Mikata A. Comedonecrosis is an unfavorable marker in node-negative invasive breast carcinoma. Pathol Int. 2003;53:501–506. doi: 10.1046/j.1440-1827.2003.01514.x. [DOI] [PubMed] [Google Scholar]
- 36.Zhang W, Gao El, Zhou YL, Zhai Q, Zou ZY, Guo GL, Chen GR, Zheng HM, Huang GL, Zhang XH. Different distribution of breast ductal carcinoma in situ, ductal carcinoma in situ with microinvasion, and invasion breast cancer. World J Surg Oncol. 2012;10:262. doi: 10.1186/1477-7819-10-262. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchió C, Reis-Filho JS. Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010;57:171–192. doi: 10.1111/j.1365-2559.2010.03568.x. [DOI] [PubMed] [Google Scholar]
- 38.To T, Wall C, Baines CJ, Miller AB. Is carcinoma in situ a precursor lesion of invasive breast cancer? Int J Cancer. 2014;135:1646–1652. doi: 10.1002/ijc.28803. [DOI] [PubMed] [Google Scholar]
- 39.Bernardi S, Bertozzi S, Londero AP, Giacomuzzi F, Angione V, Dri C, Carbone A, Petri R. Nine years of Experience with the Sentinel Lymph Node Biopsy in a Single Italian Center: A Retrospective Analysis of 1,050 Cases. World J Surg. 2012;36:714–722. doi: 10.1007/s00268-011-1420-0. [DOI] [PubMed] [Google Scholar]
- 40.Bertozzi S, Londero AP, Giacomuzzi F, Angione V, Carbone A, Petri R, Bernardi S. Applicability of two different validated models to predict axillary non-sentinel lymph node status by sentinel node biopsy in a single Italian center. Breast Cancer. 2015;22:350–5. doi: 10.1007/s12282-013-0485-z. [DOI] [PubMed] [Google Scholar]
- 41.van la Parra RF, Peer PG, Ernst MF, Bosscha K. Meta-analysis of predictive factors for non-sentinel lymph node metastases in breast cancer patients with a positive SLN. Eur J Surg Oncol. 2011;37:290–299. doi: 10.1016/j.ejso.2011.01.006. [DOI] [PubMed] [Google Scholar]