Risk factors for breast cancer from benign breast disease in a diverse population.

BACKGROUND: The majority of studies have reported risks of breast cancer (BC) from benign breast disease (BBD) in essentially homogenous Caucasian populations. Information on breast cancer risk factors in larger, multi-ethnic populations should facilitate the development of appropriate and targeted risk reduction strategies. DESIGN: Cases and controls were drawn from a parent BBD cohort of 4,970 women, 1,341 African-Americans (AA) and 3,629 non-AA who were diagnosed with BBD after examination of an excisional breast biopsy. Risk factors (34 variables) included demographics, lesion types, and epidemiological variables. RESULTS: The final multivariable model retained significance (P < 0.05) for lesion risk-level, fibroadenoma, and the interaction of age-by-race. Women with proliferative lesions (no atypia, risk level 2) were 1.7 times more likely to develop BC when compared with women with non-proliferative lesions (OR = 1.7, 95% CI 1.13, 2.42, P = 0.009). Women with atypia (risk level 3) were 3.75 times more likely to develop BC compared to women with non-proliferative lesions (OR = 3.75, 95% CI 1.99, 7.06, P < 0.001). The odds of breast cancer was approximately 35% lower among women with fibroadenoma as compared to women without fibroadenoma (OR = 0.65, 95% CI 0.46, 0.94, P = 0.020). AA women with BBD who were 50 years or older were 2.28 times more likely to develop breast cancer as compared to non-AA women who were less than 50 years old (OR = 2.28, 95% CI 1.34, 3.88, P = 0.002). CONCLUSION: Women with fibroadenoma (nonproliferative or proliferative) were less likely to progress to BC. Older AA women are at greater risk for progression to breast cancer from BBD.

Multiplicity of benign breast lesions is a risk factor for progression to breast cancer.

PURPOSE: Benign breast disease (BBD) in women encompasses a broad spectrum of histopathologic lesions. Studies on BBD have focused on the risks for subsequent breast cancer associated with three broad categories of lesions, classified as nonproliferative, proliferative, or proliferative with atypia, without addressing the issue of the contribution of concurrent multiple BBD lesions. There is very limited information with regard to the issue of BBD lesion multiplicity and breast cancer risk. EXPERIMENTAL DESIGN: We evaluated a detailed microscopic spectrum of 18 BBD lesions from fibrosis to atypical hyperplasia in a BBD cohort of 4,544 subjects, within which 4.5% (n = 201) developed breast cancer during an average follow-up period of 10.3 years. Lesions were defined as nonproliferative (8 diagnoses; risk level 1 = no risk or low risk), proliferative without atypical hyperplasia (8 diagnoses; risk level 2 = intermediate risk), and proliferative with atypical hyperplasia (2 diagnoses; risk level 3 = highest risk level). Twenty variables including age (> or =50 or <50 years) at the time of BBD diagnosis and race (African American or non-African American) were assessed. A categorical variable, surrogate for lesion type and number, was represented initially by four levels: 1, nonproliferative = 1 (reference); 2, nonproliferative > 1; 3, proliferative = 1; and 4, proliferative > 1. RESULTS: The majority of BBD subjects in our cohort (almost 70%) had more than one BBD lesion. Concurrent multiple nonproliferative or proliferative BBD lesions with or without atypia in a BBD biopsy and age are significant predictors of risk for progression of BBD to breast cancer. The presence of atypical hyperplasia in a BBD biopsy alone or in conjunction with other lesions without atypia conferred higher risks. Women with fibrosis had a reduced risk for progression to breast cancer. Race was not a significant predictor of progression to breast cancer. The effect of age, fibrosis, and multiple lesions (whether nonproliferative, proliferative, or atypia) on breast cancer progression was not influenced by race. CONCLUSION: BBD lesion multiplicity is frequent, and teasing out the heterogeneity of multiple concurrent BBD lesions is warranted to refine and improve risk estimates for progression of breast cancer from BBD.

E-cadherin status in breast cancer correlates with histologic type but does not correlate with established prognostic parameters.

Our objective was to assess the loss of E-cadherin (EC) as a diagnostic marker or a predictor of prognosis. We stained 276 breast carcinomas with monoclonal antibodies to EC (invasive lobular carcinomas [ILC] and variants, 59; invasive ductal carcinoma and ductal special types [IDC], 204; tubulolobular carcinoma [TLC], 4; and invasive carcinoma [IC], uncertain whether lobular or ductal type, 9). The results were as follows: EC+IDCs, 99.5%; EC-ILCs, 90%; EC+ILCs, 10%; EC+pleomorphic ILCs, 20%; EC-ICs, 44%. All 4 TLCs showed positive tubules while cords were negative. Statistically a correlation of EC loss with a positive diagnosis of ILC was found but there was no correlation with any prognostic tumor variables. A negative EC stain confirms the diagnosis of ILC (specificity, 97.7%; negative predictive value, 96.8%; sensitivity, 88.1%; positive predictive value, 91.2%). EC is helpful in classifying cases with indeterminate histologic features. EC loss is uncommon in nonlobular carcinomas with no correlation to currently established prognostic variables.

Molecular classification of breast carcinoma in situ.

Pleomorphic variant of invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular carcinoma (ILC). Its in situ counterpart, pleomorphic lobular carcinoma in situ (PLCIS) is a recently described entity. Morphologically it has the typical architectural pattern of LCIS, but the neoplastic cells resemble intermediate grade DCIS. Molecular signatures that distinguish PLCIS from DCIS and LCIS would provide additional tools to aid in the histopathologic classification of PLCIS as a lesion distinct from LCIS and DCIS. CIS lesions, obtained from a study cohort of 38 breast cancer patients, were divided into 18 DCIS, 14 PLCIS and 6 LCIS. DNA from microdissected archival tissue was interrogated for loss or gain of 112 breast-cancer-specific genes using the Multiplex Ligation-dependent Probe Amplification Assay (MLPA). Classification Regression Tree (CART) analysis was employed to develop a gene-based molecular classification to distinguish or separate out PLCIS from DCIS and LCIS. Molecular classification via CART, based on gene copy number, agreed with histopathology in 34/38 CIS cases. Loss of CASP1 was predictive of LCIS (n=4) with one misclassified PLCIS. Gain of RELA predicted only the LCIS classification (n=2 cases). STK15 and TNFRSF1B were predictive only for DCIS with no misclassifications. Gain of EHF and TNFRSF1B and loss of NCOA3 were predictive of PLCIS, but not without misclassification. Molecular reclassification by CART was accomplished in 4 CIS cases: 1 PLCIS was reclassified as LCIS, 1 LCIS reclassified as PLCIS, and 2 DCIS cases as PLCIS. This study provides additional rationale for molecular modeling strategies in the evaluation of CIS lesions. This diagnostic aid may serve to minimize misclassification between PLCIS and DCIS, and PLCIS and LCIS, aiding to increase accuracy in the differential diagnosis of CIS lesions.

Mammographic Localization Biopsy for Ductal Carcinoma In Situ: A Simple Mapping Technique for Sampling and Size Estimation.

Size, grade, margin status, and microscopic invasion are currently significant parameters for management of ductal carcinoma in situ (DCIS). Size estimation of DCIS is difficult or impossible if tissue is sampled haphazardly. Histologic examination of the entire biopsy to exclude microscopic invasion is cumbersome and expensive, and may not yield more information than less extensive but planned sampling. One hundred twenty-four mammographic localization biopsies with DCIS including 4 cases with 3 mm or less invasion are presented to address these issues. All were examined by a mapping technique utilizing specimen radiograph as a guide for sampling and a schematic drawing to record the sections. This involved sequential sampling of the entire tissue for smaller biopsies, and en bloc sampling of the mammographic abnormality and surrounding tissue with end-to-end sampling of the remaining tissue at regular intervals for larger biopsies. All tissue was examined histologically initially in 55 cases, while tissue away from the lesion was selectively omitted in 71 cases. To address the issue of occult invasion, all initially unsampled tissue of 44 biopsies was submitted for histologic examination after completion of the case and the findings were recorded separately. Size estimates ranged from 4 to 70 mm. The solitary focus of microscopic invasion in four cases was present in the initial sections at the site corresponding to the mammographic abnormality. No invasion was identified in the additional tissue in any of the 44 cases. Margin status did not change for any. Using specimen radiographs as a guide, all the necessary information for DCIS, including the size and microscopic invasion, can be obtained by a planned sampling of tissue with diagrammatic documentation. Sequential sections of the entire tissue for small biopsies and sampling at regular intervals to include tissue at and around the mammographic abnormality for larger biopsies is appropriate. Microscopic invasion, when focal, is likely to be identified at the site of mammographic abnormality in the initial en bloc sections.

Delineating an epigenetic continuum for initiation, transformation and progression to breast cancer.

Aberrant methylation of promoter CpG islands is a hallmark of human cancers and is an early event in carcinogenesis. We examined whether promoter hypermethylation contributes to the pathogenesis of benign breast lesions along a progression continuum to invasive breast cancer. The exploratory study cohort comprised 17 breast cancer patients with multiple benign and/or in situ lesions concurrently present with invasive carcinoma within a tumor biopsy. DNA from tumor tissue, normal breast epithelium when present, benign lesions (fibroadenoma, hyperplasia, papilloma, sclerosing adenosis, apocrine metaplasia, atypical lobular hyperplasia or atypical ductal hyperplasia), and in situ lesions of lobular carcinoma and ductal carcinoma were interrogated for promoter methylation status in 22 tumor suppressor genes using the multiplex ligation-dependent probe amplification assay (MS-MLPA). Methylation specific PCR was performed to confirm hypermethylation detected by MS-MLPA. Promoter methylation was detected in 11/22 tumor suppressor genes in 16/17 cases. Hypermethylation of RASSF1 was most frequent, present in 14/17 cases, followed by APC in 12/17, and GSTP1 in 9/17 cases with establishment of an epigenetic monocloncal progression continuum to invasive breast cancer. Hypermethylated promoter regions in normal breast epithelium, benign, and premalignant lesions within the same tumor biopsy implicate RASSF1, APC, GSTP1, TIMP3, CDKN2B, CDKN2A, ESR1, CDH13, RARB, CASP8, and TP73 as early events. DNA hypermethylation underlies thepathogenesis of step-wise transformation along a monoclonal continuum from normal to preneoplasia to invasive breast cancer.

Benign breast disease heterogeneity: association with histopathology, age, and ethnicity.

BACKGROUND: Benign breast biopsies with concurrent multiple benign lesions with different histopathologic diagnoses were termed heterogeneous benign breast disease (HBBD). Multiplicity of benign breast disease (BBD) lesions in a biopsy is a risk factor for progression to breast cancer (BC). Elucidation of the biological characteristics and clinical implications of HBBD may also be relevant to the refinement of risks for BC in women with a BBD diagnosis. DESIGN: In this study, we investigated the association of HBBD with histopathology, age, and ethnicity. A cohort of 4,341 women, 1,208 African Americans and 3,133 Caucasians, diagnosed with BBD, was identified after examination of an excisional breast biopsy. BBD biopsies were categorized as nonproliferative (NP, low risk or risk 1 lesions), proliferative without atypia (P, intermediate risk or risk 2 lesions), and proliferative with atypia (AH, high risk or risk 3 lesions). A BBD biopsy with only a single BBD lesion was termed simple BBD (SBBD). BBD biopsies with multiple lesions were further classified as single level HBBD (SL-HBBD) if the concurrent lesions were within the same risk level, or as multiple level HBBD (ML-HBBD) if lesions fell into more than one risk group. RESULTS: In this cohort, 69% of women with a BBD diagnosis fit the HBBD criteria. Among women with HBBD, ML-HBBD was almost three times more prevalent than SL-HBBD and was significantly more likely to be composed of risk 2 and risk 3 lesions. The likelihood of HBBD was 57% higher in Caucasian American women than in African American women with BBD (OR 1.57; 95% CI: 1.37, 1.81). The average lesion number in HBBD was directly proportional to increasing lesion risk (P < 0.001). Compared to women with risk 1 lesions, the likelihood of HBBD was 5.59 (95% CI: 4.85-6.44) and 17.0 (95% CI: 10.2-28.5) times higher when risk 2 and risk 3 lesions, respectively, were present. Women in the age range of 46-55 years and >55 years had a 3.12 (95% CI: 2.59, 3.75) and a 2.28 (95% CI: 1.94, 2.68) fold higher likelihood of HBBD compared to those < or =45 years. Significant interaction was found between concurrent lesion levels and age (P < 0.01). The likelihood of HBBD was considerably higher across all age groups for risk 3 lesions. Compared to the reference (risk 1, age < or =45), the likelihood of HBBD for risk 2 lesions was 4.4 times greater (95% CI: 3.70, 5.33) in women < or =45 YEARS, BUT THAT LIKELIHOOD INCREASED TO 17.6 (95% CI: 12.8, 24.2) AND 13.4 (95% CI: 10.1, 17.9) TIMES IN WOMEN OF 46-55 AND >55 YEARS, RESPECTIVELY. CONCLUSION: HBBD is more prevalent in Caucasian American women than in African American women. Women with higher risk BBD lesions are more likely to have HBBD. Lesion number and higher risk BBD lesions are significantly correlated with ML-HBBD. Additionally, the associations of HBBD and lesion risk level are modified by age.

Advanced stages and poorly differentiated grade are associated with an increased risk of HER2/neu positive breast carcinoma only in White women: findings from a prospective cohort study of African-American and White-American women.

OBJECTIVE: The primary objective of this study was to evaluate the race-specific risk associated with HER2/neu positive breast carcinoma in a prospective cohort design. Our secondary objectives were to assess prevalence of different breast cancer phenotypes between African-American and White women and to determine if race was associated with the risk of basal-like breast carcinoma phenotype in this cohort. METHODS: Demographic, clinical and pathologic data were collected from existing databases. The status of HER2/neu and hormone receptors was dichotomized as either positive or negative. Immunohistochemistry taxonomy was used to assess prevalence of different breast carcinoma phenotypes. Risk estimates were calculated using the multivariable logistic regression statistics. CONCLUSIONS: The risk of HER2/neu positive breast carcinoma differs between African-American and White women. For White women only, this risk was statistically significant and increased almost linearly within each TNM stage with grade dedifferentiation. The statistically significantly higher prevalence of "ER(-)/PR(-), HER2(- )" phenotype in African American women potentially is the attributing factor to observed lack of an association between the risk of HER2/neu positive breast carcinoma with advanced stages and poorly differentiated grade. Among women diagnosed with "ER(-)/PR(-), HER2(-)" phenotype the odds ratios of being African-American and pre-menopausal was 1.72 (95% CI 1.17-2.54, P = 0.006) and 1.94 (95% CI 1.27-2.96, P = 0.002), respectively. The histologic features of basal-like and ER(-)/HER2(+ )carcinomas overlaps. Differences in the biology of breast carcinoma between African American and White women are partially attributed to the disparity in more adverse pathologic prognostic indicators at the initial clinical presentation of this disease.

Breast cancer incidence in a cohort of women with benign breast disease from a multiethnic, primary health care population.

Women with benign breast diseases (BBD), particularly those with lesions classified as proliferative, have previously been reported to be at increased risk for subsequent development of breast cancer (BC). A cohort of 4970 women with biopsy-proven BBD, identified after histopathology review of BBD biopsies, was studied for determination of subsequent development of BC. We report on 4537 eligible women, 28% of whom are African-American, whose BBD mass was evaluable for pathologic assessment of breast tissue. Ascertainment of subsequent progression to BC from BBD was accomplished through examination of the tumor registries of the Henry Ford Health system, the Detroit SEER registry, and the State of Michigan cancer registry. Incidence rates (IR) are reported per 100,000 person years at risk (100 k pyr). Poisson regression models were used to evaluate the association of demographic and lesion characteristics with BC incidence, using person years at the time of BBD diagnosis as the offset variable. The estimated overall BC IR for this cohort is 452 (95% confidence interval [CI] = 394-519) per 100 k pyr. Incidence for women age 50 and older is 80% greater than for younger women (p = 0.007, IRR = 1.8, 95% CI = 1.36-2.36). Neither marital status (p = 0.91, IRR = 0.97, 95% CI = 0.73-1.29) nor race (p = 0.67, IRR = 0.9, 95% CI = 0.54-1.48) is associated with differences in BC IR. Compared with women having nonproliferative lesions, the risk for BC is greater for women with atypical ductal hyperplasia of (IRR = 5.0; 95%CI = 2.26-11.0; p < 0.001) and other proliferative lesions (IR = 1.7, 95% CI = 1.02-2.95; p = 0.04). BC risk for woman with atypical lesions is significantly higher than for women with proliferative lesions without atypia (IRR = 2.58, 95% CI = 1.35-4.90; p = 0.0039). Neither race nor marital status was a factor for BC incidence from BBD in this cohort. Age retained its importance as a predictor of risk. BBD lesion histopathology in the outcome categories of either proliferative without atypia or proliferative with atypia are significant risk factors for BC, even when adjusted for the influence of demographic characteristics. The risks associated with BBD histological classifications were not different across races.

Evaluating post-treatment screening in women with breast cancer.

PURPOSE: The objective of this study was to evaluate the 5-year post-treatment use rate for screening mammography and clinical breast examination (CBE) among women treated for atypical hyperplasia (AH) or carcinoma in situ (CIS). DESCRIPTION OF STUDY: A total of 103 women, who had received diagnoses and had been treated for primary AH or CIS, were observed for 5 years through a review of medical records and electronic databases. Adequate screening use was defined as the patient undergoing one mammography examination and at least one CBE per year. RESULTS: Multivariate logistic regression showed that screening activity declined significantly with time. During the first year, 83.5% and 80.6%, respectively, of women were screened by CBE and mammography. By year 2, CBE screening had dropped by 25.2% (P <.01) and mammography screening by 9.7% (P =.08). Attrition in CBE and mammography screening continued for each consecutive year and was significant (P <.01). During the first year, 70.9% of women received both methods of screening, which declined to 9.7% by year 5. Women who had received diagnoses of CIS and those married with children were more likely to use post-treatment screening, while fee-for-service insurance was negatively associated with screening. CLINICAL IMPLICATIONS: The reasons for the observed decline in the annual post-treatment screening are not known. Negative findings from follow-up screenings might have lowered the perception of cancer susceptibility and promoted the decline in screening use. A communication gap between physicians and patients might have reinforced this perception. The importance of annual screening may be verbally emphasized at each clinic visit, and reminder notes and telephone calls may be used to remind patients of upcoming screenings. Additional studies are planned to evaluate the effect of various intervention strategies in improving post-treatment screening use.

False-negative core needle biopsies of the breast: an analysis of clinical, radiologic, and pathologic findings in 27 concecutive cases of missed breast cancer.

BACKGROUND: A benign diagnosis in a core needle biopsy (CNBx) of the breast performed for a clinically and/or radiologically suspicious abnormality is often due to a nonrepresentative sample. However, the discordance may not be recognized, resulting in a logistic delay in the diagnosis. METHODS: Twenty-seven false-negative CNBxs were identified in 952 consecutive CNBxs of the breast (653 benign, 266 malignant, and 33 atypical) performed during a 1-year period. Biopsies were analyzed with respect to clinical and radiologic findings, biopsy type, type of malignancy, and interval between the original CNBx and final diagnosis. Four hundred thirty-eight (67%) of the patients with a benign CNBx diagnosis either underwent excision or had a minimum of 1-year follow-up (mean, 35.6 months; median, 36 months). RESULTS: The cancers missed on CNBx included 6 ductal carcinomas in situ, 17 invasive ductal carcinomas, 3 invasive lobular carcinomas, and 1 non-Hodgkin lymphoma. The overall false-negative rate was 9.1%. For palpable lesions, ultrasound-guided CNBx had a lower rate of missed cancer (3.6%) compared with CNBx without image guidance (13.3%). The false-negative rate for vacuum assisted CNBx biopsy was 7.6% (3.3% for the 11-gauge needle, 22.2% for the 14-gauge needle; 5.6% for nonpalpable mass lesions, 8.2% for microcalcifications). In all seven false-negative CNBxs performed by radiologists, the discordance between the radiologic and pathologic findings was promptly recognized due to their standard follow-up protocol. The discordance between the degree of clinical suspicion, radiologic impression, and the pathologic findings was not immediately recognized in 5 of 20 false-negative CNBxs performed by surgeons (4 without radiologic guidance and 1 with ultrasound guidance), resulting in a delay in the diagnosis ranging from 112-336 days. CONCLUSIONS: A false-negative diagnosis of breast carcinoma was found to be more common in CNBx performed without image guidance but occurred to a lesser degree in image-guided biopsies. A delay in diagnosis can be avoided by establishing a standard post-CNBx follow-up protocol.

Establishing a molecular continuum in breast cancer DNA microarrays and benign breast disease.

Although the risk of breast cancer for women in the United States is approximately 1 in 9, identification of risk factors and translation of that knowledge into strategies for prevention have been inhibited by poor understanding of disease pathogenesis. A few benign breast proliferations are associated with higher risks of breast cancer, but definition of a preneoplastic morphologic continuum is lacking. If progression from a premalignant state to malignancy is accompanied by genetic changes, then identification in benign breast disease lesions (BBD) of alterations similar to those found in breast cancer should strengthen the perception of BBD as a premalignant condition. Current testing for hereditary breast cancer susceptibility presumes that only women with invasive breast or ovarian cancer are gene carriers. Therefore, neither in situ breast cancer nor atypical hyperplasias are considered clinically as evidence of a breast-ovarian syndrome, nor are these diagnoses used to predict carrier status within at-risk families. This reflects lack of evidence that breast cancer develops along a recognized morphologic continuum from precursor lesions. New mutation screening procedures such as DNA microarrays can provide sensitivity, specificity, and high throughput that circumvent limitations imposed on the scope of molecular marker analyses applied to archival resources. We have studied a BRCA1-mutant individual with loss of the wild type BRCA1 allele in benign breast proliferations. Both her benign and malignant lesions showed molecularly identical TP53 mutations, indicating that significant genetic alterations can occur in BBD and supporting the clonal evolution from BBD to malignancy.

Primary cutaneous mucinous carcinoma: presence of myoepithelial cells as a clue to the cutaneous origin.

BACKGROUND: Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy with probable apocrine differentiation. It is important to differentiate it from metastatic mucinous carcinoma (MMC), especially from the breast. The histologic and immunohistochemical features overlap between PCMC and breast mucinous carcinomas. In this study, we introduce the presence of myoepithelial component in PCMC as a new morphologic parameter to distinguish it from MMC from either breast or sites elsewhere in the body. MATERIALS AND METHODS: We studied 7 cases of PCMC. The possible in situ component in the tumor was assessed by the presence of a peripheral myoepithelial cell layer. Myoepithelial cell differentiation was confirmed with immunohistochemical stains for p63, CK 5/6, calponin, smooth muscle actin (SMA), HHF-35, and CD10. Estrogen and progesterone receptor (ER/PR), gross cystic disease fluid protein (GCDFP 15), CK7, CK20, and S-100 immunostains were also performed. RESULTS: Histologically, multiple small monomorphic epithelial islands floating in multilocular pools of mucin characterized the tumor. Focally, epithelial islands were bordered by dermal connective tissue at the periphery of mucin pools. Secretory snouts were apparent in all cases providing evidence for apocrine differentiation. In 5 of the 7 cases, an in situ component was identified as epithelial islands being bounded by a myoepithelial layer, which was highlighted by p63, CK 5/6, calponin, SMA, and HHF-35. ER/PR and CK7 were positive in all the cases. GCDFP-15 and CD10 were focally positive in the tumor cells and myoepithelial cells, respectively. All 7 cases were negative for S-100 and CK 20. CONCLUSION: We conclude that an in situ component is frequently present in PCMC (5/7) and may help in distinguishing this entity from MMC, especially of breast origin. Furthermore, it may provide insight into the pathogenetic mechanism of mucinous carcinoma evolving from in situ carcinoma with luminal mucinous distention to cellular tumor with a little surrounding mucin.