Noncomedo Ductal Carcinoma In Situ Research Articles

Correlations of ER, PR, Her-2 and CK5/6 expression with histological characteristics features and prognosis of breast ductal carcinoma in situ

This study aimed to investigate the correlations of Estrogen Receptor (ER), Progesterone Receptor (PR), human epidermal growth factor receptor 2 (Her-2) and cytokeratin 5/6 (CK5/6) protein expression with histological characteristics features and prognosis of breast Ductal Carcinoma in situ (DCIS). Fortyeight cases of breast DCIS specimen were enrolled in this study. The samples were histologically typed and graded. The immunohistochemical analysis was performed to determine the expression of ER, PR, Her-2 and CK5/6 protein. Results showed that, the positive rates of ER and PR protein expression in non-comedo type DCIS group were significantly higher than those in comedo type DCIS group, respectively (P 0.05). There was significant difference of positive rate of ER, PR, Her-2 protein expression among histological grades I-III (P 0.05). The expression of ER protein was positively correlated with PR protein expression (r=0.764, P<0.001) and negatively correlated with Her-2 protein expression (r=-0.643, P<0.001); the expression of PR protein was negatively correlated with Her-2 protein expression (r=-0.622, P<0.001). In 4 recurrent DCIS cases, Her-2 protein expression was positive in 3 cases. ER, PR and CK5/6 protein expressions were negative in all 4 cases. In conclusion, ER, PR, Her-2 protein expressions are significantly correlated with the histological types and histological grades of breast DCIS. The positive Her-2 protein expression is related to the prognosis of breast DCIS.

Complete Regression of Ductal Carcinoma in Situ Following Chemotherapy and Trastuzumab: Should we Rethink Management?

Background: Ductal carcinoma in situ (DCIS) includes comedo-DCIS, which consists of high-grade DCIS associated with dilated ducts filled with intraluminal comedonecrosis. Current consensus opinion is that prognosis is excellent for all forms of DCIS and that no form of DCIS responds to chemotherapy. However, herein we describe a patient who had complete resolution of comedo-DCIS with the combination of paclitaxel, carboplatin and trastuzumab and results of a retrospective analysis that challenge current opinion. Materials and methods: The cancer registry of Hoag Hospital in Newport Beach, California, was used to indentify subset cohorts of patients with DCIS and local- stage invasive breast cancer. Survival curves were compared by the log-rank test. Results: There were 7,373 breast cancer patients diagnosed during 1983-2007 including 205 classified as comedo-DCIS, 1006 as non-comedo-DCIS, 46 as locally invasive comedocarcinoma and 3905 as other types of locally invasive breast cancer. Ninety-eight percent of the comedocarcinoma diagnoses were made prior to 1997. During 1991-2000 comedo-DCIS accounted for 134/505 (26.5%) of all DCIS compared to 61/565 (10.8%) during 2001-2007 (p<0.0001). Patients with comedo-DCIS had a worse overall survival than other DCIS patients (p<0.040), but survival was similar for comedo-DCIS and invasive comedocarcinoma (p=0.62). Conclusion: Neoadjuvant chemotherapy plus trastuzumab can completely eradicate Her2-positive comedo-DCIS. Survival for comedo-DCIS is worse than for non-comedo DCIS and similar to invasive comedocarcinoma. Because of changes in synoptic reporting and current terminology in pathology reports, comedocarcinoma is no longer being documented and the diagnosis of comedo- DCIS has decreased. Additional studies are warranted to determine whether women with large breast lesions that show only comedo-DCIS on biopsy, should be considered candidates for neoadjuvant therapy to facilitate breast-conserving surgery.

Abstract C46: Racial disparities in risk of second breast tumors after ductal carcinoma in situ: A population-based analysis

Abstract Importance: The impact of race and ethnicity on second breast tumors among women with ductal carcinoma in situ (DCIS) has not been well defined. Objective: To examine racial disparity in DCIS outcomes according to clinical characteristics of tumors. Design, Setting, and Patients: Data from 18 US Surveillance, Epidemiology and End Results registries included 102,489 women diagnosed with primary unilateral DCIS from 1988 through 2009 (white 73.6%, black 9.7%, Asian 9.0%, and Hispanic 7.7%). Patients undergoing mastectomy (n=31,899) were excluded from the analysis of ipsilateral breast recurrence. Main Outcomes and Measures: Relative risks (RRs) and their 95% confidence intervals (CI) of ipsilateral breast recurrence and contralateral breast tumors adjusted for pathologic factors, treatment, age at the diagnosis of DCIS, year of diagnosis, and registry. Results: Among 74,809 women treated with breast conserving surgery or with no surgical treatment, 2,925 (3.9%) developed ipsilateral breast recurrence during a median follow-up of 66 months. Compared with white women, black (RR=1.46; 95% CI, 1.29-1.65) and Hispanic (RR=1.18; 95% CI, 1.03-1.36) women experienced elevated risk of ipsilateral recurrence, which was similar for invasive cancer vs DCIS. A significant increase in risk of ipsilateral recurrence among black women persisted, regardless of age at the diagnosis of DCIS, treatment, tumor grade, tumor size, and histology. Overall, 3,723 (3.6%) of 102,489 women with DCIS developed contralateral breast tumors during a median follow-up of 70 months. The risk for contralateral breast tumors was significantly increased among black (RR=1.21; 95% CI, 1.08-1.36) and Asian (RR=1.16; 95% CI, 1.02-1.31) women compared with white women. Such association depended on type of events (Pheterogeneity&amp;lt;.0001); it was stronger for invasive cancer vs DCIS among black women and for DCIS vs invasive cancer among Asian women. The elevated risk of contralateral breast tumors associated with black race was more obvious among women ≥50 years at the diagnosis of DCIS and those with comedo DCIS; in contrast, a significant increase in risk among Asian women was restricted to those&amp;lt;50 years at the diagnosis of DCIS and those with noncomedo DCIS. Conclusions and Relevance: Black women with DCIS had disproportionately excess risks of second breast tumors in the ipsilateral and contralateral breasts, which could not be explained by pathologic features and treatment. The elevated risk of ipsilateral recurrence among black and Hispanic women suggests their need for more intensive follow-up and surveillance. Citation Format: Ying Liu, Graham Colditz. Racial disparities in risk of second breast tumors after ductal carcinoma in situ: A population-based analysis. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C46. doi:10.1158/1538-7755.DISP13-C46

Racial disparities in risk of second breast tumors after ductal carcinoma in situ.

The purpose of the study was to examine the impact of race/ethnicity on second breast tumors among women with ductal carcinoma in situ (DCIS). We identified 102,489 women diagnosed with primary DCIS between 1988 and 2009 from the 18 NCI-SEER Registries. Cox proportional hazard regression was used to estimate race/ethnicity-associated relative risks (RRs) and their 95% confidence intervals (CI) of ipsilateral breast tumors (IBT; defined as DCIS or invasive carcinoma in the ipsilateral breast) and contralateral breast tumors (CBT; defined as DCIS or invasive carcinoma in the contralateral breast). Overall, 2,925 women had IBT and 3,723 had CBT. Compared with white women, black (RR 1.46; 95% CI 1.29-1.65), and Hispanic (RR 1.18; 95% CI 1.03-1.36) women had higher IBT risk, which was similar for invasive IBT and ipsilateral DCIS. A significant increase in IBT risk among black women persisted, regardless of age at diagnosis, treatment, tumor grade, tumor size, and histology. The CBT risk was significantly increased among black (RR 1.21; 95% CI 1.08-1.36) and Asian/PI (RR 1.16; 95% CI 1.02-1.31) women compared with white women. The association was stronger for invasive CBT among black women and for contralateral DCIS among Asian/PI women (P heterogeneity<0.0001). The black race-associated CBT risk was more pronounced among women ≥50years at diagnosis and those with comedo DCIS; in contrast, a significant increase in risk among Asian/PI women was restricted to those <50years and those with noncomedo DCIS. Racial/ethnic differences in risks of second breast tumors after DCIS could not be explained by pathologic features and treatment.

Abstract P1-15-09: Ductal Carcinoma In Situ of the Breast: Clinico-Pathological Features Predicting Residual Disease in Postlumpectomy Re-Excision Specimens

Abstract INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, which often grows discontinuously within the breast tissue. Younger age, residual mammographic microcalcifications, positive surgical margins, tumor size, nuclear grade and architectural type are consistently related to ipsilateral breast tumor recurrence in DCIS. To re-excise or not when a lumpectomy margin is close is a controversial issue for breast pathologists, surgeons and oncologists, and often no residual disease is found when a re-excision is performed. The aim of this study is to investigate the clinico-pathological features of DCIS that might predict residual disease in the re-excision specimen in patients treated by lumpectomy with either positive or close margins. METHODS: Consecutive patients with DCIS who required postlumpectomy re-excision either for positive or for close margins were selected in this retrospective analysis. Close margin was defined as less than 0.1 cm. The initial lumpectomy specimens were examined for tumor size, architectural type, nuclear grade and margin status, and patient age was considered. The subsequent re-excision specimens were analyzed for residual disease. The clinico-pathological features of original lumpectomy specimens were correlated with the presence or absence of residual DCIS in the re-excision specimens. Logistic regression statistical test was used to determine if any of these clinico-pathological features predicted the presence or absence of DCIS in the subsequent re-excision specimens. RESULTS: There were 37 cases of DCIS without accompanying invasive carcinoma that had positive or close resection margins (positive margin n=8; 21.6%, close margin n=29; 78.4%). Age of the patients ranged from 30 to 93 years. DCIS present in the original lumpectomy specimen was comedo type with necrosis n=8; 21.6% and non-comedo type n-29; 78.4%. Twenty-one lumpectomy specimens (57%) exhibited more than one type of DCIS. Four tumors were nuclear grade 1 (10.8%). 17 were nuclear grade 2 (45.9%), and 16 were nuclear grade 3 (43.2%). Residual DCIS was present in 20 out of 37 (54.1%) re-excision specimens. Six out of 8 (75%) comedo DCIS had residual disease, compared to 14 out of 29 (48.3%) non-comedo DCIS. Eleven out of 20 patients (55%) with residual disease were younger than 60 years. The correlation of patient age and type of DCIS to residual disease in the re-excision specimens was short of statistical significance due to small size of study sample (p value = 0.178 and 0.175 respectively). There was no statistically significant association between nuclear grade and distance to margin with residual disease in re-excision specimens (p value = 0.757 and 0.734 respectively). CONCLUSION: Younger age and comedo type DCIS may be important factors in predicting residual disease in the re-excision specimens. If this can be confirmed in a larger, multi-institutional data set, there could be a more tailored selection of who needs a re-excision. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-15-09.

MDCT Is Very Useful for Evaluating the Spread of DCIS.

Abstract Introduction: Ductal carcinoma in situ (DCIS) may occasionally spread widely in the duct-lobular segment, thereby complicating the complete resection of the lesion in breast-conserving surgery. In order to perform a safe operation for DCIS, the lesion area must be precisely evaluated in the preoperative imaging studies. We performed multidetector-row computed tomography (MDCT) for patients with DCIS and investigated the potential of MDCT for detecting DCIS lesions.Patients and methods: A total of 74 patients with DCIS underwent MDCT. The size of the DCIS lesion in each patient was measured in the volume-rendering view, and these sizes were compared with the lesion sizes obtained by mapping from the pathological tests. The differences between the lengths obtained from pathological tests and those obtained from MDCT (L-path-L-CT) were calculated, and the relationships between the differences and some factors were investigated.Results: Among the 74 DCIS patients who underwent MDCT, DCIS was detected in 61 patients (82.4%). Among these 61 cases, 45.8% were cases of comedo-type DCIS, but the detection rates for comedo and noncomedo cases were not different. The L-path-L-CT values for histological grade I DCIS (1.55 cm) and grade II &amp; III DCIS (0.23 cm) were statistically different. Higher-grade DCIS was more detectable than low-grade DCIS (p = 0.013). Among the other factors, the MDCT assessments and the pathological assessments for comedo-type DCIS and Her-2-positive cases were more consistent than the corresponding results for noncomedo DCIS and Her-2-negative cases. However, these differences were not significant.Conclusion: MDCT shows high efficiency in detecting DCIS. More aggressive types of DCIS, such as higher grade, comedo type, and Her-2-positive DCIS were more precisely detected by MDCT. In comparison with magnetic resonance imaging (MRI), the patient's position during MDCT testing is more similar to that during surgery. Therefore, MDCT is a highly useful presurgical imaging technique for the assessment of DCIS. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5029.

Reproductive and hormonal risk factors for ductal carcinoma in situ of the breast.

One-fifth of all newly diagnosed breast cancer cases are ductal carcinoma in situ (DCIS), but little is known about DCIS risk factors. Recent studies suggest that some subtypes of DCIS (high grade or comedo) share histopathologic and epidemiologic characteristics with invasive disease, whereas others (medium or low grade or non-comedo) show different patterns. To investigate whether reproductive and hormonal risk factors differ among comedo and non-comedo types of DCIS and invasive breast cancer (IBC), we used a population-based case-control study of 1,808 invasive and 446 DCIS breast cancer cases and their age and race frequency-matched controls (1,564 invasive and 458 DCIS). Three or more full-term pregnancies showed a strong inverse association with comedo-type DCIS [odds ratio (OR), 0.53; 95% confidence interval (95% CI), 0.30-0.95] and a weaker inverse association for non-comedo DCIS (OR, 0.73; 95% CI, 0.42-1.27). Several risk factors (age at first full-term pregnancy, breast-feeding, and age at menopause) showed similar associations for comedo-type DCIS and IBC but different associations for non-comedo DCIS. Ten or more years of oral contraceptive showed a positive association with comedo-type DCIS (OR, 1.31; 95% CI, 0.70-2.47) and IBC (OR, 2.33; 95% CI, 1.06-5.09) but an inverse association for non-comedo DCIS (OR, 0.51; 95% CI, 0.25-1.04). Our results support the theory that comedo-type DCIS may share hormonal and reproductive risk factors with IBC, whereas the etiology of non-comedo DCIS deserves further investigation.

Comparison of magnetic resonance imaging, multidetector row computed tomography, ultrasonography, and mammography for tumor extension of breast cancer

Breast imaging modalities can assess the tumor extent and adequacy of excision, but there have been no reports comparing magnetic resonance (MR) imaging, multidetector row computed tomography (MDCT), ultrasonography (US) and mammography (MMG) for the tumor extent of breast cancer. We prospectively assessed the accuracy of MR imaging, MDCT, US and MMG for preoperative assessment of the tumor extent of breast cancer. Preoperative MR imaging, MDCT, US and MMG were performed for 210 breasts with breast cancer. The MR and MDCT images were independently interpreted by one of two radiologists with knowledge of the clinical and MMG findings. The US was performed with knowledge of the clinical and MMG findings by one of five US technologists. The correlation of the results of these examinations with histological findings was examined. Of the 210 index breast tumors, 210 (100%) could be detected on MR, 208 (99%) were detected on MDCT, 209 (99.5%) were detected on US, and 195 (93%) were detected on MMG. For evaluating local tumor extent, the accuracy of MR imaging (76%) was significantly higher than those of MDCT, US, and MMG (71%, 56%, and 52%, respectively) (P = 0.001, P < 0.0001, and P < 0.0001). MDCT was significantly more accurate than US (P < .0001) or MMG (P < .0001), and US was significantly more accurate than MMG (P = 0.004). MR imaging and US had substantial risk (11% and 17%) of overestimation of the tumor extent. Regarding ductal carcinoma in situ (DCIS), for non-comedo DCIS, the accuracies of MR imaging (89%), MDCT (72%), and US (61%) were significantly higher than the 22% accuracy of MMG (P < 0.0001, P = 0.012, and P = 0.016), but for comedo DCIS, there were no significant differences among the four breast imaging modalities. MR imaging was the most accurate breast imaging modality for the tumor exten of breast cancer, although MR imaging had a substantial of risk of overestimation. MR imaging, MDCT and US can complement MMG for the preoperative evaluation of patients who are candidates for breast-conserving surgery.

MRI of the Breast for the Detection and Assessment of the Size of Ductal Carcinoma in Situ

ObjectiveThe aim of the study was to compare the accuracy of magnetic resonance imaging (MRI) and mammography for the detection and assessment of the size of ductal carcinoma in situ (DCIS).Materials and MethodsThe preoperative contrast-enhanced MRI and mammography were analyzed in respect of the detection and assessment of the size of DCIS in 72 patients (age range: 30-67 years, mean age: 47 years). The MRI and mammographic measurements were compared with the histopathologic size with using the Pearson's correlation coefficients and the Mann-Whitney u test. We evaluated whether the breast density, the tumor nuclear grade, the presence of comedo necrosis and microinvasion influenced the MRI and mammographic size estimates by using the chi-square test.ResultsOf the 72 DCIS lesions, 68 (94%) were detected by MRI and 62 (86%) were detected by mammography. Overall, the Pearson's correlation of the size between MRI and histopathology was 0.786 versus 0.633 between mammography and histopathology (p < 0.001). MRI underestimated the size by more than 1 cm (including false negative examination) in 12 patients (17%), was accurate in 52 patients (72%) and overestimated the size by more than 1 cm in eight patients (11%) whereas mammography underestimated the size in 25 patients (35%), was accurate in 31 patients (43%) and overestimated the size in 16 patients (22%). The MRI, but not the mammography, showed significant correlation for the assessment of the size of tumor in noncomedo DCIS (p < 0.001 vs p = 0.060). The assessment of tumor size by MRI was affected by the nuclear grade (p = 0.008) and the presence of comedo necrosis (p = 0.029), but not by the breast density (p = 0.747) or microinvasion (p = 0.093).ConclusionMRI was more accurate for the detection and assessment of the size of DCIS than mammography.

Ductal Carcinoma in situ of the Breast. Comparison between the Van Nuys Classification and Nottingham Classification.

Background : Assessment of the biological malignancy of DCIS is important as a factor related to indications for breast-conserving therapy and subsequent stump recurrence. We assessed the biological malignancy of each grade in the Van Nuys (VN) Classification and the Nottingham (Nott) Classification. Methods : The surgical specimens from 24 patients with DCIS were examined. Immonohistochemistry was used to assess the expression of ER, p53, Ki-67 (MIB-1), and Her2/nue in the tumor cell of 24 patients with DCIS. We classified DCIS by VN and Nott systems and compared Grade 3 tumors with the other grades (Grade 1 and 2).Results : VN Grade 3 (VN3) DCIS had high ER-negative (P=0.01) and P53-positive (P=0.05) rates, and frequently had a high Ki67 1. I. (P=0.03). Three of the 4 specimens highly positive for Her2/nue (P=0.08) were VN3. The Nott Grade 3 (Nott3) specimens were all ER-negative (P=0.03) and frequently P53-positive (P=0.04), and all had a high Ki67 L. I (P=0.04). Similar to VN3 DCIS, 3 of the 4 specimens highly positive for Her2/nue (P=0.003) were Nott3. However, 3 specimens that were judged to be nuclear grade (NG) 3 noncomedo type DCIS and VN3 were classified as Nott 1 and 2, not Nott 3. Of these 3 specimens, 2 were ER-negative, 1 was p53 positive, and 2 had a high Ki67 L. I., indicating that non-Nott 3 cancer is not necessarily low-malignant. Conversely, all Nott3 cancers were classified as VN3.Conclusion : The results suggested that the nuclear-grade-based VN system may be a more reliable classification in terms of grade of malignancy that the histological-type-based Nott systems.

Sentinel lymph node biopsy for localised ductal carcinoma in situ?

Intraductal carcinoma of the breast (DCIS), by definition, cannot give axillary metastases. Axillary dissection is therefore not indicated. The role of the sentinel lymph node (SLN) biopsy in the management of DCIS has not yet been established. A 6-13% risk of SLN involvement is reported in Literature. The aim of the present study is to assess the role of SLN biopsy in patients with pure DCIS and attempt to identify guidelines for routine practice in managing such patients. From March 1996 to December 2003, 508 consecutive patients with pure DCIS of the breast underwent SLN biopsy at the European Institute of Oncology in Milan. Clinical and pathological data were prospectively collected. In all cases of previous surgery or stereotactic biopsy performed elsewhere all pathological slides were reviewed. Cases with microinvasion were excluded from this investigation. Lymphatic mapping was performed using a radiocolloid technique. Most of the patients underwent conservative surgery and removal of the SLN which was sent for conclusive histology. SLN metastases were detected in 9 out of 508 (1.8%) patients. In five patients only micrometastasis (<2 mm) was detected. Eight patients underwent complete axillary dissection. In none of these patients did we find additional positive axillary lymph nodes. In conclusion, due to the low prevalence of metastatic involvement (1.8%), SLNB should not be considered a standard procedure in the treatment of all patients with DCIS. In pure non-comedo DCIS completely excised by radical surgery with free margins of resection SLNB should be avoided since not only it is unnecessary but could also jeopardize a successive re-SLNB in case of invasive recurrence. A very extensive and accurate histological examination of the tumour in DCIS is compulsory to exclude micro-invasive foci and, finally, to decrease the prevalence of unexpected SLN metastases. SLNB should be considered in case of DCIS where there exists a strong doubt of invasion at the definitive histology, such as large solid tumours or diffuse or pluricentric microcalcifications undergoing mastectomy. Moreover, if the trend is statistically confirmed with a wider population, large comedo-DCIS, presenting superior risk of SLNs metastasis, could be scheduled for SLNB. If the SLN is micrometastatic complete axillary dissection is not unavoidable.

Age-Specific Incidence Rates of In situ Breast Carcinomas by Histologic Type, 1980 to 2001

Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have increased rapidly over the past several decades largely due to the increased use of mammography. However, recent data from 1987 to 1999 indicate that invasive ductal carcinoma incidence rates have remained essentially constant, whereas rates of invasive lobular carcinoma have increased 65%, with greater increases observed among postmenopausal women. Data on recent trends in DCIS and LCIS incidence rates, particularly age-specific trends, are lacking. We evaluated trends in the incidence rates of DCIS overall, noncomedo DCIS, comedo DCIS, and LCIS using data from nine Surveillance, Epidemiology, and End Results cancer registries. DCIS incidence rates increased 7.2-fold [95% confidence interval (95% CI), 6.8-7.7] from 1980 to 2001, 1.8-fold (95% CI, 1.7-1.9) over the past 10 years (1992-2001), and 1.1-fold (95% CI, 1.0-1.2) over the past 5 years (1997-2001). The magnitudes of these increases were highest among women ages > or = 50 years. Furthermore, over the past 10- and 5-year periods, rates of noncomedo DCIS have generally increased across all age groups, whereas rates of comedo DCIS held constant or decreased. LCIS incidence rates increased 2.6-fold (95% CI, 2.3-2.9) from 1980 to 2001, 1.3-fold (95% CI, 1.2-1.5) over the past 10 years, and 1.1-fold (95% CI, 1.0-1.3) over the past 5 years. Similar to invasive lobular carcinoma, but unlike invasive ductal carcinoma, incidence rates of both DCIS and LCIS continue to increase in the United States primarily among older women. These trends present important public health and clinical challenges.

Ductal carcinomain situ and related lesions of the breast: Recent advances in pathology practice

The incidence of ductal carcinoma in situ (DCIS) of the breast has increased significantly in Japanese women. It comprises 14.1% (172/1216) of all primary breast cancers at our institute, and nowadays this histological type is familiar to the surgeons and pathologists of any institute. Several subclassifications have been published recently. Most based on nuclear atypia and the presence of comedonecrosis, and sometimes on the structures of the involved glands. These classifications are correlated with the biological behavior, tumor extent and the risk for local recurrences. The diagnostic accuracy of minimally invasive procedures (aspiration biopsy cytology/core needle biopsy) may differ between subclasses. Atypical ductal hyperplasia (ADH) and microinvasive ductal carcinomas are lesions which resemble but deviate from the DCIS spectrum. The incidence of ADH seems to be lower than in Western countries. Patients with ADH may have a risk for subsequent breast cancer, because ADH is frequently associated with contralateral breast carcinomas. Microinvasion should be treated with caution, but we could not find any metastatic foci in microinvasive ductal carcinomas (T1mic). Tentatively, ADH may be treated similarly to non-comedo (low-grade) DCIS cases, according to our limited clinical experience.

Expression and amplification of cyclin D1 in primary breast carcinomas: Relationship with histopathological types and clinico-pathological parameters

Overexpression and amplification of cyclin D1 were investigated by immunohistochemistry and differential polymerase chain reaction (dPCR) in 440 formalin-fixed primary breast carcinoma tissues. Overexpression of cyclin D1 was detected in 60% (263/440) and amplification of cyclin D1 was noted in 27% (119/440) of the primary breast carcinomas. Molecular analysis demonstrated that cyclin D1 was amplified in 30% (7/23) of the comedo DCIS, 22% (9/41) of the comedo DCIS and 32% (13/41) of the adjacent invasive ductal carcinomas, 30% (82/270) of the invasive ductal carcinomas, 27% (9/33) of the invasive lobular carcinomas, 19% (4/21) of the colloid carcinomas and 13% (2/15) of the medullary carcinomas. Cyclin D1 was amplified in 11% (2/19) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions. Our observation showed that cyclin D1 was strongly positive in 61% (14/23) of the comedo subtype, 61% (11/18) of the non-comedo subtype, 59% (24/41) of the comedo DCIS and 63% (26/41) of the adjacent invasive ductal carcinomas, 53% (10/19) of the non-comedo DCIS and 58% (11/19) of the adjacent invasive lesions, 58% (157/270) of the invasive ductal carcinomas, 73% (24/33) of the invasive lobular carcinomas, 52% (11/21) of the colloid carcinomas and 27% (4/15) of the medullary carcinomas. A significant association was observed between in situ components and adjacent invasive lesions for cyclin D1 expression (p<0.05) and amplification (p<0.05). A significant relationship was noted between amplification of cyclin D1 and lymph node metastases (p<0.05) but not with histological grade (p>0.05), estrogen receptor status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). However, overexpression of cyclin D1 was statistically associated with well differentiated tumors (p<0.05) and estrogen receptor positivity (p<0.05). No relationship was seen with nodal status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). These observations suggest that tumors positive for cyclin D1 protein may have features of good prognosis but amplification of cyclin D1 gene could be an indicator of tumors with poor prognostic features. Although majority of the Malaysian patients belong to younger age group (<50 years old), amplification and expression of cyclin D1 was not statistically associated with patient age (p>0.05). These observations indicate that amplification and up-regulation of cyclin D1 may be independent of patient age. Moreover, overexpression and amplification of cyclin D1 in preinvasive, preinvasive and adjacent invasive lesions, and invasive carcinomas suggest that the gene may play an important role in early and late stages of breast carcinogenesis.

Protein expression and molecular analysis of c-myc gene in primary breast carcinomas using immunohistochemistry and differential polymerase chain reaction

Overexpression of c-myc protein and amplification of c-myc were investigated by immunohistochemistry and differential polymerase chain reaction (dPCR) in 440 formalin-fixed primary breast carcinoma tissues, respectively. Overexpression of c-myc was detected in 45% (199/440) and amplification of c-myc was observed in 25% (112/440) of the primary breast carcinomas. Immunolocalization of c-myc oncoprotein was demonstrated in 35% (8/23) of the comedo subtype, 17% (3/18) of the non-comedo subtype, 37% (15/41) of the comedo DCIS and 49% (20/41) of the adjacent invasive ductal carcinomas, 21% (4/19) of the non-comedo DCIS and 37% (7/19) of the adjacent invasive lesions, 49% (133/270) of the invasive ductal carcinomas, 33% (11/33) of the invasive lobular carcinomas, 29% (6/21) of the colloid carcinomas and 47% (7/15) of the medullary carcinomas. C-myc was amplified in 13% (3/23) of the comedo DCIS, 17% (7/41) of the comedo DCIS and 24% (10/41) of the adjacent invasive ductal carcinomas, 30% (82/270) of the invasive ductal carcinomas, 21% (7/33) of the invasive lobular carcinomas, 14% (3/21) of the colloid carcinomas and 24% (4/15) of the medullary carcinomas. Amplification of c-myc was noted in 16% (3/9) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions. A significant association (P<0.05) was observed between in situ components and adjacent invasive lesions for c-myc expression and amplification. Overexpression of c-myc protein was significantly correlated with poorly differentiated (P<0.05) and high proliferation index (Ki-67) (P<0.05) tumors but not with lymph node metastases (P>0.05), patient age (P>0.05) and estrogen receptor status (P>0.05). Significant relationship was also noted between amplification of c-myc and absence of estrogen receptor (P<0.05), high histological grade (P<0.05) and high proliferation index (Ki-67) (P<0.05). No relationship was seen with nodal status (P>0.05) and patient age (P>0.05). Majority of the Malaysian female patients are from younger age group (<50 years old) but overexpression and amplification of c-myc was not statistically associated with patient age (P>0.05) indicating that these alterations may be independent events of patient age. The above observations suggest that overexpression and amplification of c-myc could play an important role in tumor progression from non-invasive to invasive and, also, it may have the potential as a marker of poor prognosis of breast cancer.

Detection of amplified int-2/FGF-3 gene in primary breast carcinomas using differential polymerase chain reaction

Amplification of int-2/FGF-3 gene was investigated by differential polymerase chain reaction (dPCR) in 440 archival primary breast carcinoma tissues. Of these, 23 were comedo ductal carcinoma in situ (DCIS), 18 were non-comedo DCIS, 41 were comedo DCIS with adjacent invasive ductal carcinomas, 19 were non-comedo DCIS with adjacent invasive ductal carcinomas, 270 were invasive ductal carcinomas, 33 were invasive lobular carcinomas, 21 were colloid carcinomas and 15 were medullary carcinomas. Int-2 was amplified in 22% (96/440) of the primary breast carcinomas. It was shown that int-2 was amplified in 13% (3/23) of the comedo DCIS, 17% (7/41) of the comedo DCIS and 29% (12/41) of the adjacent invasive ductal carcinomas, 26% (71/270) of the invasive ductal carcinomas, 18% (6/33) of the invasive lobular carcinomas, 10% (2/21) of the colloid carcinomas and 13% (2/15) of the medullary carcinomas. In contrast, int-2 was not amplified in non-comedo DCIS and invasive ductal carcinomas with adjacent non-comedo DCIS lesions. A significant association was observed between int-2 amplification in the in situ components and adjacent invasive lesion (P<0.05). All tumors with int-2 amplification in the in situ lesions (7/7) also demonstrated same degree of amplification in the adjacent invasive components. However, 9% (5/53) of the tumors with no amplified int-2 gene in the in situ components showed int-2 amplification in the adjacent invasive lesions. A significant relationship was noted between amplification of int-2 and lymph node metastases (P<0.05) and poorly differentiated tumors (P<0.05) but not with estrogen receptor status (P>0.05) and proliferation index (Ki-67 and PCNA) (P>0.05). In Malaysia, majority of the patients belong to younger age group (<50 years old) but a comparison of the age groups showed that the amplification of int-2 was not statistically associated with patient age (P>0.05). These observations indicate that amplification of int-2 tends to strengthen the view that int-2 may have the potential to be an indicator of poor prognosis regardless of the age of the patient. Moreover, the presence of int-2 amplification in preinvasive, preinvasive and adjacent invasive lesions, and invasive carcinomas suggest that int-2 could be a marker of genetic instability occurring in early and late stages of tumor development.

Mammary Endocrine Ductal Carcinoma in Situ: A Case Report

Endocrine differentiation represents a pathway of neoplastic development available to a range of breast cancers. This pattern occurs in tumors with different morphological appearances as ductal carcinoma in situ (DCIS), mucinous carcinoma, a variant of lobular carcinoma, and low-grade invasive ductal carcinoma. Endocrine ductal carcinoma in situ is an uncommon entity. It occurs in older women with a mean age of 70 years. Histologically it shows expansile intraductal growth forming solid sheets and festoons transversed by delicate fibrovascular septa. Conventional microscopy permits the diagnosis in most cases. Specialized techniques such as immunohistochemistry and electron microscopy can serve as the basis of diagnosis in the absence of the appropriate morphological features. We present a 68-year-old female with a 1.5-cm firm mobile nodule of the left breast. Mammography and ultrasounds showed a 15 x 15-mm circumscribed solid lobulated nodule. The mass was excised and pathology was positive for endocrine DCIS. Although endocrine DCIS has a biologic marker profile similar to that of well-differentiated or noncomedo DCIS it may constitute a different histogenetic pathway of carcinogenesis in the breast. The tumor may exhibit the invasive characteristics of a neuroendocrine neoplasm. Larger studies and longer follow-up are needed for the determination of the clinical behavior.

Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci.

Usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) are risk factors for invasive breast cancer (IBC), suggesting that these lesions may be direct precursors of IBC. To identify genetic changes that may be important in the early development of precursor lesions and their progression to malignant or invasive disease, we examined 399 putative precursors (211 UDH, 51 ADH, 81 non-comedo DCIS, and 56 comedo DCIS) for loss of heterozygosity (LOH) at 15 polymorphic genetic loci known to exhibit high rates of loss in IBC. We also assessed the sharing of LOH by putative precursors and synchronous cancers. The polymerase chain reaction was used to analyze DNA from microdissected archival specimens. In hyperplasias from noncancerous breasts (i.e., without DCIS and/or IBC in analyses of hyperplasias), LOH at any given locus was rare (range, 0%-15%), although 37% of UDH and 42% of ADH lesions showed loss for at least one locus, suggesting that the development of hyperplasias can involve many different tumor suppressor genes. In DCIS from noncancerous breasts (i.e., without IBC in analyses of DCIS), LOH was common, with 70% of noncomedo lesions and 79% of comedo lesions showing at least one loss. In DCIS, substantial rates of loss (up to 37%) were observed at loci on chromosomes 16q, 17p, and 17q, suggesting that inactivated tumor suppressor genes in these regions may be important in the development of noninvasive breast cancer. When DCIS lesions from cancerous and noncancerous breasts were compared, substantially more LOH was observed in the cancerous breasts at a few loci (on chromosomes 2p, 11p, and 17q), suggesting that genetic alterations in these regions may be important in the progression to invasive disease. Among specimens harvested from cancerous breasts, 37% of UDH, 45% of ADH, 77% of noncomedo DCIS, and 80% of comedo DCIS lesions shared LOH with synchronous cancers at one locus or more, supporting the idea that the putative precursors and the cancers are genetically related.

The Results of Conservative Surgery and Radiation for Mammographically Detected Ductal Carcinoma In Situ

: Approximately 85% of all ductal carcinoma in situ (DCIS) are now detected by mammographic screening. For the most part, the literature that reported the results of conservative surgery and radiation for DCIS reflected outcomes in a heterogeneous patient population that frequently included patients with clinically evident DCIS (palpable mass or bloody nipple discharge). There are limited data regarding outcome in patients with mammographically detected DCIS treated with conservative surgery and radiation. The 10-year breast recurrence rate ranges from 4% to 7% for patients with negative margins of resection with a 10-year cause-specific survival of 96–100%. Factors that have been associated with an increased risk of breast recurrence include the failure to remove all malignant appearing calcifications prior to radiation and positive margins of resection. The influence of young age and positive family history on breast recurrence rates requires further study. To date there has been little correlation with the pathologic features of DCIS (architectural pattern, necrosis, nuclear grade) and breast recurrence rates in patients receiving radiation. Comedo or high nuclear grade DCIS tends to recur at a shorter median interval than noncomedo or low nuclear grade DCIS. Approximately 50% of the recurrences are invasive and salvage mastectomy has resulted in long-term control in 100% of the noninvasive recurrences and approximately 80% of the invasive recurrences.

Assessment of hormone dependence of comedo ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) represents 20%-30% of breast cancers detected by clinical screening (i.e., mammography). More than 50% of DCIS lesions may be estrogen receptor negative and, therefore, hormone independent. However, the role of estrogen in the natural history of DCIS is unknown. A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth. Specimens of breast tissue were collected from 52 women during diagnostic or therapeutic surgical procedures. Portions of each specimen were randomly selected and analyzed by histology and thymidine labeling (to measure cell proliferation). The remainder of each specimen was implanted into five to 18 athymic BALB/c nu/nu mice (depending on the amount of tissue available), with eight pieces of approximately 2 mm x 2 mm x 1 mm implanted at different locations on the back of each mouse. Half of the mice received implants containing estrogen (2 mg 17 beta-estradiol), and the other half received placebo implants. Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specific for the Ki-67 nuclear antigen. Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens. Serum 17 beta-estradiol levels in the mice were measured by radioimmunoassay. Initial levels of cell proliferation were approximately 10-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versus 1.9%, respectively; two-sided P < .001). Xenografts from the majority of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation. Estrogen treatment of the xenograft-bearing mice had no effect on the high level of cell proliferation observed in estrogen receptor-negative, comedo DCIS specimens (two-sided P = .89). In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001). However, even with estrogen treatment, cell proliferation levels in estrogen receptor-positive DCIS specimens did not reach those seen in estrogen receptor-negative DCIS specimens. Estrogen receptor-negative, comedo DCIS lesions appear to be estrogen independent; therefore, antiestrogen (e.g., tamoxifen) therapy may not benefit patients with comedo DCIS.