Columnar Cell Hyperplasia Research Articles

Abstract GS01-06: Advancing Evidence of the Associations Between Specific Benign Breast Diagnoses and Future Breast Cancer RIsk

Abstract Background: Benign breast disease (BBD) is a common breast biopsy finding encompassing a diverse spectrum of diagnoses. Breast cancer risk associated with many specific BBD diagnoses and their joint associations with breast density have not been extensively studied. We estimate the future risk of invasive breast cancer associated with specific BBD diagnoses typically categorized into the broad category of proliferative lesions without atypia (PWoA) and evaluate whether associations differ by breast density or by presence of calcifications. Methods: We included 1,313,943 women ages 40-79 years who underwent 5,282,063 mammograms in the Breast Cancer Surveillance Consortium from 1996 to 2019 with no prior history of breast cancer. We fit a Cox proportional hazards model to estimate hazard ratios associated with each combination of PWoA BBD diagnoses, whether calcifications were present on biopsy, and breast density. We used classification trees to group combinations of PWoA diagnoses, breast density, age groups, and presence of calcifications with similar magnitudes of associations with 5-year risk of invasive breast cancer. Results: Compared with women with a PWoA BBD diagnosis without calcifications, presence of calcifications significantly elevated risk for breast cancer (HR=1.19, 95% CI = 1.02 to 1.41, P=0.03). Considering specific PWoA diagnoses, classification trees identified groups of women with higher and lower invasive cancer risk than expected risk for all PWoA combined. Among women ages 60-79 years with heterogeneously or extremely dense breasts, the 2.6% of women with any PWoA diagnosis, except papillomatosis, were at high invasive breast cancer risk (5-year risk >2.5%) (Table 1). Among women ages 40-59 years with dense breasts, presence of calcifications with papillomas, usual ductal hyperplasia, columnar cell hyperplasia, or PWoA NOS diagnoses put these women at high risk (5-year risk >2.5%) compared to women with the same BBD diagnoses without calcifications who were at intermediate or average risk (1-2.49%) (Table 1). Among women ages 60-79 years with non-dense breasts, the 1.6% of women with papilloma, usual ductal hyperplasia, radial scar, or PWoA NOS diagnoses were at high breast cancer risk (Table 2). Among women ages 40-59 years with non-dense breasts, presence of calcifications with usual ductal hyperplasia or PwoA NOS diagnoses put these women at intermediate risk (1.67-2.49%) compared to women with these BBD diagnoses without calcifications who were at average risk (1-1.66%) (Table 2). Women 60-79 years with fatty breasts were at intermediate 5-year risk if they had papillomas, usual ductal hyperplasia, or PWoA NOS diagnoses. Women 40-59 years with fatty breasts were at low risk of breast cancer regardless of PWoA diagnosis (Table 2). Conclusion: Specific BBD diagnoses and the presence of calcifications can change a woman’s predicted 5-year breast cancer risk compared to broad BBD categories alone. This information could be incorporated into risk prediction models to improve model accuracy. Citation Format: Olivia Sattayapiwat, Karla Kerlikowske, Donald Weaver, Alexander Borowsky, Theresa Keegan, Brian Sprague, Diana Miglioretti. Advancing Evidence of the Associations Between Specific Benign Breast Diagnoses and Future Breast Cancer RIsk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-06.

In Search of Calcifications : Histologic Analysis and Diagnostic Yield of Stereotactic Core Needle Breast Biopsies.

Stereotactic core needle biopsy (SCNB) is used in the diagnostic assessment of suspicious mammographic calcifications to rule out breast ductal carcinoma in situ (DCIS). With advances in imaging technology and increased biopsy tissue volume, the detection rate of calcifications and DCIS in SCNB is unclear. This retrospective study included 916 consecutive SCNBs for calcifications performed on 893 patients in a 2-year period. We found the cancer detection rate was 27.1% (DCIS, 23.7%; invasive, 3.4%). The detection rate for calcifications was 74.8% with the standard 3 levels. Additional leveling of calcification-negative cases further increased the detection of both calcifications (to 99.4% of cases) and DCIS (to 32.9% of cases). Lobular neoplasia (LN) was diagnosed in 41 cases. Twenty-five (61.0%) cases of LN were incidental without associated calcification. Of 32 invasive carcinomas detected on SCNB, 87.5% were T1a or less, and calcifications were associated with atypical ductal hyperplasia/DCIS or LCIS. The common benign lesions associated with calcifications were fibrocystic change (32.5%), fibroadenomatous change (30.2%), and columnar cell change and hyperplasia (8.2%). We determined the up-to-date detection rates of calcification and DCIS in SCNB, as well as the common benign and malignant breast lesions associated with calcifications. Additional levels significantly increase the detection rate when standard levels show only stromal or scant/absent calcifications. Lobular neoplasia is often an incidental finding in SCNB for calcifications. When calcifications are present with LN, they are commonly florid, pleomorphic LCIS, or with concurrent invasive carcinoma.

Are Columnar Cell Lesions the Earliest Non-Obligate Precursor in the Low-Grade Breast Neoplasia Pathway?

Columnar cell lesions (CCLs) of the breast comprise a spectrum of morphologic alterations of the terminal duct lobular unit involving variably dilated and enlarged acini lined by columnar epithelial cells. The World Health Organization currently classifies CCLs without atypia as columnar cell change (CCC) and columnar cell hyperplasia (CCH), whereas flat epithelial atypia (FEA) is a unifying term encompassing both CCC and CCH with cytologic atypia. CCLs have been increasingly recognized in stereotactic core needle biopsies (CNBs) performed for the assessment of calcifications. CCLs are believed to represent the earliest non-obligate precursor of low-grade invasive breast carcinomas as they share molecular alterations and often coexist with entities in the low-grade breast neoplasia pathway. Despite this association, however, the risk of progression of CCLs to invasive breast carcinoma appears low and may not exceed that of concurrent proliferative lesions. As the reported upgrade rates of pure CCL/FEA when identified as the most advanced high-risk lesion on CNB vary widely, the management of FEA diagnosed on CNB remains controversial. This review will include a historical overview of CCLs and will examine histologic diagnostic criteria, molecular alterations, prognosis and issues related to upgrade rates and clinical management.

Clinicopathological analysis of seven breast hamartomas and review of the literature

Aim: Breast hamartomas are uncommon benign lesions that constitute 4.8% of benign breast tumors; they consist of mammary ducts and lobules, fatty tissue, and fibrous tissue. The aim of this study was to determine the clinical and pathological characteristics of breast hamartomas diagnosed by surgical resection and to examine the accompanying lesions. Material and Methods: Patients who underwent breast surgery between January 2013 and January 2018 at Konya Education and Research Hospital and who were diagnosed as having breast hamartomas were reviewed retrospectively. Results: Seven breast hamartomas were identified. All of them were female. The mean age was 45 years. The mean tumor size was 3.9 cm. Most of the lesions were located in the right breast (57.1%). All the hamartomas appeared in the upper part of the breast. Five of the seven cases were admitted with a painless palpable mass in the breast (71.4%). Three of the seven cases were myoid hamartomas. The type of lesion most commonly associated with breast hamartomas is cyst formation. Pseudoangiomatous stromal hyperplasia, columnar cell hyperplasia, and ductal epithelial hyperplasia are also common. Ductal epithelial hyperplasia and columnar cell hyperplasia were observed in all the myoid hamartomas. Ductal carcinoma in situ was detected in one case; it was also a myoid hamartoma. Conclusions: Breast hamartomas are accompanied by many types of lesions such as fibrocystic changes, adenosis, ductal epithelial hyperplasia, and pseudoangiomatous stromal hyperplasia. In addition to these lesions, columnar cell hyperplasia was also identified. Malignancies are rarely detected in breast hamartomas; however, one case of ductal carcinoma in situ in a myoid hamartoma was detected.

Étude anatomoclinique et immunohistochimique d’une tumeur dérivant des glandes ano-génitales de type mammaire : l’hidradénome papillifère

To specify the clinical, histopathological and immunochemical features in a large series of hidradenoma papilliferum patients and to point out similarities with breast disease. We performed a monocentric retrospective histopathological study. Cases of hidradenoma papilliferum seen at the dermatopathology laboratory of Strasbourg (1977-2017) were included and analyzed with hematoxylin-eosin staining and immunostaining. Diagnosis was confirmed where tubular formations and papillary proliferations were noted and were lined by a luminal layer of columnar cells surrounded by a basal layer of myoepithelial cells. We included 32cases solely involving women of a mean age of 49years. Most cases involved the vulva (67%) or the perianal region (25%). The lesions ranged in size from 3to 25mm. They occurred as solitary, non-ulcerated, skin-colored and cyst-like lesions. They were mostly localized in the mid-dermis. We identified several peculiar morphological variants. Three HP had a structure resembling tubular apocrine papillary adenoma, 3were similar to apocrine cystadenoma, while 9HP, of which 3involved epidermal hyperplasia, were connected with the overlying epidermis and had dense stromal infiltrate in plasma cells, closely resembling syringocystadenoma papilliferum. Sixteen tumors had no features of note. Similarities with breast tumors were revealed through columnar cell hyperplasia (6cases), high mitotic rates (4cases), and atypical nuclei (3cases). Anogenital mammary-like glands were found in the immediate vicinity of 10HP. Myoepithelial cells were immunoreactive for smooth muscle actin and p63, while luminal cells were immunoreactive for CK7, CK8, EMA, and, in a more focused and less consistent manner, for Ber-EP4, CD117, PHLDA1and androgen receptors. Our study highlighted a variety of patterns and cell morphologies, on occasion within a single tumor, identical to breast disease. Histological and immunochemical examination revealed that anogenital mammary-like glands and HP share common features, which militates in favor of a common histogenesis.

A study of incidence of columnar cell lesions in neoplastic and non –neoplastic lesions of breast

Background: Columnar cell lesions of breast are increasingly being encountered in breast biopsies because of their associated micro calcifications which are detected on mammographic screening.Observational studies suggest the co-existence of Columnar cell lesions with more advanced lesions of breast like Ductal carcinoma in situ,Atypical ductal hyperplasia and Invasive carcinoma. The presence of Columnar cell lesionneeds careful search for otheratypical breast lesionsin proximity. Aim: To study the occurrence of Columnar cell lesions in Neoplastic and NonNeoplastic breast lesions and evaluate the type of lesion with respect to category of breast lesion.Materials and methods: This is an observational study conducted in the Department of Pathology,Gandhi hospitalfrom January 2016 to December 2017.H&E stained sections of Neoplastic and Non-Neoplastic breast lesions were reviewed andassociated Columnar cell changes were evaluated.Results:Total200 breast lesions were studiedout of which 134 showed Columnar cell lesions. 90% cases of fibrocystic disease and 60% of fibroadenoma cases were associated with CCL and the predominant type of lesionis Columnar cell change. 80% cases of Ductal carcinoma insituand 40% of Infiltrative duct cell carcinoma cases showed CCL and the common lesion is Columnar cell hyperplasia without atypia.Conclusion: Columnar cell lesions were observed in both Neoplastic and Non-Neoplastic breast lesions. Based on previous observational studies cancer risk associated with CCL is only mild on long term follow up. However detection of CCL in biopsy should prompt additional scrutiny for other pathological changes.

Selected abbreviations and new terms in breast pathology — a guide for clinicians

The aim of this article is to present briefly new pathological entities which are recently increasingly commonly used in pathology reports, as well as to discuss their clinical consequences. The new WHO classification of breast diseases includes, inter alia , invasive carcinoma of no special type: this is not a specific entity, but rather a group of malignancies without specific features. The lobular hyperplasia group includes a classical variant and a pleomorphic variant of lobular carcinoma in situ, as well as atypical lobular hyperplasia. The ductal hyperplasia group, according to the current revision of the WHO classification of breast diseases, encompasses: typical (i.e. non-atypical) ductal hyperplasia, columnar cell change, columnar cell hyperplasia, atypical ductal hyperplasia. The mesenchymal breast hyperplasia group includes pseudoangiomatous stromal hyperplasia. We briefly discuss the above mentioned entities together with their respective clinical and therapeutic consequences.

Anogenital Mammary-Like Glands: A Study of Their Normal Histology With Emphasis on Glandular Depth, Presence of Columnar Epithelial Cells, and Distribution of Elastic Fibers.

The normal histology of anogenital mammary-like glands (AGMLG) has been studied previously, but some aspects, including glandular depth, presence of columnar epithelium resembling columnar cell change/hyperplasia as defined in mammary pathology, and distribution of elastic fibers, have not been previously investigated. To address these issues, we studied 148 AGMLG identified in 133 paraffin blocks sampled from 64 vulvar wide excision or vulvectomy specimens (64 patients, various indications for surgery). The depth of AGMLG ranged from 0.64 to 3.9 mm. Epithelial columnar cell change was noted in 33.1% of all AGMLG, whereas columnar cell hyperplasia was detected in 10.1%. Occasionally, combinations of cuboidal epithelium and columnar cell change were seen within 1 histological section. Of 22 specimens stained for elastic fibers, in only 6 (27.3%) cases were elastic fibers found around glands. Periductal elastic fibers were demonstrated around 3 of the only 5 ducts, which were available for analysis in slides stained for elastic fibers. The depth of AGMLG should be taken into account when planning topical and surgical therapies for lesions derived or evolving from AGMLG. Alterations identical to columnar cell change may represent a normal variation of AGMLG.

Spectrum of Changes in Anogenital Mammary-like Glands in Primary Extramammary (Anogenital) Paget Disease and Their Possible Role in the Pathogenesis of the Disease.

To determine whether a subset of primary extramammary Paget disease (EMPD) may originate in anogenital mammary-like glands (AGMLG), the authors studied 181 specimens of EMPD, detailing alterations in AGMLG. The latter were identified in 33 specimens from 31 patients. All patients were women, ranging in age from 38 to 93 years (median, 65 y). In all cases, lesions involved the vulva and in 1 patient the perianal skin was affected. Histopathologically, AGMLG manifested changes identical to columnar cell change (CCC) (87.1%), usual ductal hyperplasia (22.6%), columnar cell hyperplasia (CCH) (9.7%), oxyphilic (apocrine) metaplasia (6.5%), and atypical duct hyperplasia (3.2%). Four cases (12.9%), in addition to intraepidermal carcinoma, harbored invasive carcinoma. In all 4 of these, AGMLG displayed a range of alterations including ductal carcinoma in situ, CCC, and CCH. Three further cases (9.7%) showed ductal carcinoma in situ without any definite invasive carcinoma. Colonization of AGMLG by neoplastic Paget cells was noted in 6 cases. As CCC and CCH may be encountered in normal AGMLG, these alterations are unlikely to play a significant role in the pathogenesis of the disease. However, by analogy with mammary Paget disease, rare cases of primary EMPD may originate in AGMLG with a subsequent upward migration of the neoplastic cells into the epidermis and possible later breach through the basal membrane. Usual ductal hyperplasia and atypical duct hyperplasia can then be regarded as earlier precursor lesions, linking both ends of the spectrum.

Surgical implications and variability in the use of the flat epithelial atypia diagnosis on breast biopsy specimens

ObjectivesFlat epithelial atypia (FEA) is a relatively new diagnostic term with uncertain clinical significance for surgical management. Any implied risk of invasive breast cancer associated with FEA is contingent upon diagnostic reproducibility, yet little is known regarding its use. Materials and methodsPathologists in the Breast Pathology Study interpreted one of four 60-case test sets, one slide per case, constructed from 240 breast biopsy specimens. An electronic data form with standardized diagnostic categories was used; participants were instructed to indicate all diagnoses present. We assessed participants' use of FEA as a diagnostic term within: 1) each test set; 2) 72 cases classified by reference as benign without FEA; and 3) six cases classified by reference as FEA. 115 pathologists participated, providing 6900 total independent assessments. ResultsNotation of FEA ranged from 0% to 35% of the cases interpreted, with most pathologists noting FEA on 4 or more test cases. At least one participant noted FEA in 34 of the 72 benign non-FEA cases. For the 6 reference FEA cases, participant agreement with the case reference FEA diagnosis ranged from 17% to 52%; diagnoses noted by participating pathologists for these FEA cases included columnar cell hyperplasia, usual ductal hyperplasia, atypical lobular hyperplasia, and atypical ductal hyperplasia. ConclusionsWe observed wide variation in the diagnosis of FEA among U.S. pathologists. This suggests that perceptions of diagnostic criteria and any implied risk associated with FEA may also vary. Surgical excision following a core biopsy diagnosis of FEA should be reconsidered and studied further.

Atypical Ductal Hyperplasia and Columnar Cell Hyperplasia of the Minor Salivary Gland: Another Mammary Analogue Lesion?

Results: Positive expression in dysplastic cells were detected in %34,4 of the cases. The distribution of the cases is as follows;%21,9 in mild dysplasia,%25 in moderate dysplasia,% 21,9 in severe dysplasia,%9,4 in carcinoma in situ, and %21,9 in carcinoma(p1⁄40,4). Foxp3 expression by dysplastic cells in selected lesions is not statistically associated with pathologic differentiation. Conclusions: In conclusion, this study demonstrated that Foxp3 was expressed in dysplastic squamous cells but not correlated with pathologic differentiation. However, further studies in larger population are needed to confirm these findings.

Epithelial and stromal microRNA signatures of columnar cell hyperplasia linking Let-7c to precancerous and cancerous breast cancer cell proliferation.

Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor α (ERα) expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the post-transcriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. Let-7c were among the identified downregulated epithelial miRNAs and its functions were delineated in unique CCH derived cells and breast cancer cell line MCF-7 suggesting anti-proliferative traits potentially due to effects on Myb and ERα. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding normal terminal duct lobular units (TDLUs), and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes of genes involved in metabolism, DNA damage and cell motility. The miRNA signatures identified in CCH indicate early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.

Inter-observer variability between general pathologists and a specialist in breast pathology in the diagnosis of lobular neoplasia, columnar cell lesions, atypical ductal hyperplasia and ductal carcinoma in situ of the breast

BackgroundThis study aimed to assess inter-observer variability between the original diagnostic reports and later review by a specialist in breast pathology considering lobular neoplasias (LN), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) of the breast.MethodsA retrospective, observational, cross-sectional study was conducted. A total of 610 breast specimens that had been formally sent for consultation and/or second opinions to the Breast Pathology Laboratory of Federal University of Minas Gerais were analysed between January 2005 and December 2010. The inter-observer variability between the original report and later review was compared regarding the diagnoses of LN, CCL, ADH, and DCIS. Statistical analyses were conducted using the Kappa index.ResultsWeak correlations were observed for the diagnoses of columnar cell change (CCC; Kappa = 0.38), columnar cell hyperplasia (CCH; Kappa = 0.32), while a moderate agreement (Kappa = 0.47) was observed for the diagnoses of flat epithelial atypia (FEA). Good agreement was observed in the diagnoses of atypical lobular hyperplasia (ALH; Kappa = 0.62) and lobular carcinoma in situ (LCIS; Kappa = 0.66). However, poor agreement was observed for the diagnoses of pleomorphic LCIS (Kappa = 0.22). Moderate agreement was observed for the diagnoses of ADH (Kappa = 0.44), low-grade DCIS (Kappa = 0.47), intermediate-grade DCIS (Kappa = 0.45), and DCIS with microinvasion (Kappa = 0.56). Good agreement was observed between the diagnoses of high-grade DCIS (Kappa = 0.68).ConclusionsAccording to our data, the best diagnostic agreements were observed for high-grade DCIS, ALH, and LCIS. CCL without atypia and pleomorphic LCIS had the worst agreement indices.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1640072350119725.

Columnar Cell Lesions Without Atypia Initially Diagnosed on Breast Needle Biopsies: Is Imaging Follow-Up Enough?

The purpose of this study was to evaluate the underestimation rate and predictive factor of underestimation of columnar cell lesions (CCLs) without atypia diagnosed through breast core needle biopsies (CNBs). From January 2007 through December 2011, 141 CCLs without atypia, including columnar cell change and columnar cell hyperplasia, were diagnosed in 138 women by CNB. Excisional (n = 16) or imaging follow-up (n = 125) findings were available in all cases. On a per-lesion basis, the underestimation rate and predictive factor of underestimation were evaluated. Among the 16 surgically excised lesions, there were two malignancies (one ductal carcinoma in situ and one invasive ductal carcinoma) and one lobular carcinoma in situ. Overall, the pooled underestimation rate of malignancy was 1.4% (2/141). With regard to lesion variables, the mean lesion size was significantly larger in the underestimation group of CCLs (p = 0.007). Fine pleomorphic morphology of microcalcifications (p < 0.001), the distribution of the microcalcifications (p = 0.007), BI-RADS final assessment (p = 0.001), and imaging-pathologic correlation (p < 0.001) were significantly associated with underestimation. Multivariate analysis showed that fine pleomorphic morphology of microcalcifications (p < 0.0001) was an independent predictor of underestimation in 58 lesions with microcalcifications on mammography. The overall underestimation rate of malignancy was 1.4%. Imaging follow-up is reasonable for CCLs without atypia at CNB, especially in small lesions with less suspicious imaging findings. Fine pleomorphic microcalcifications and higher BI-RADS category might be helpful in the prediction of underestimation of a high-risk lesion or malignancy.

Signet ring lobular carcinoma in situ as a part of the &amp;#8220;rosen triad&amp;#8221; (tubular carcinoma, columnar cell hyperplasia, and lobular carcinoma in situ)

The association of tubular carcinoma, columnar cell lesions and lobular carcinoma in situ, also known as the "Rosen Triad", may be encountered in breast biopsies performed for evaluation of mammographically detected microcalcifications. A case in which tubular carcinoma and columnar cell hyperplasia were associated with a histologically unusual form of signet ring lobular carcinoma in situ is presented. Signet ring non-invasive lobular carcinoma is classified as high-grade lobular carcinoma in situ, but herein is associated with changes that belong to the molecular pathway of low-grade mammary neoplasia. We reported the case of lobular carcinoma in situ associated with columnar cell hyperplasia and tubular carcinoma, in which the lobular carcinoma in situ was presented in a histologically unexpected form comprised predominantly of signet ring cells.

P2-06-04: Phosphatidylinositol-3-Kinase Pathway Mutations Are Common in Breast Columnar Cell Lesions.

Abstract The phosphatidylinositol-3-kinase pathway is one of the most commonly mutated in invasive breast carcinoma, with PIK3CA mutations present in ∼25% of invasive carcinomas, and AKT1 mutations identified in up to 5%. Several studies have demonstrated the same complement of mutations in ductal carcinoma in-situ (DCIS), as well as benign papillomas. We sought to investigate whether PIK3CA mutations occur in breast columnar cell lesions (CCL). Twenty-five breast resection specimens containing CCL (including columnar cell change, columnar cell hyperplasia, and flat epithelial atypia) were identified from the files of Stanford University Pathology; 15 of these had associated invasive carcinoma (IDC) or carcinoma in situ. DNA was prepared from punches of formalin-fixed paraffin-embedded tissue blocks using standard methods. DNA extracts were screened for a panel of point mutations using a multiplex PCR panel with a mass-spectroscopy readout (Sequenom MassARRAY). The panel covers 321 mutations in 30 genes, including ABL, AKT1/2/3, BRAF, CDK4, CTNNB1, EGFR1, ERBB2, FBX4, FBXW7, FGFR1/2/3, FLT3, GNAQ, HRAS, JAK2, KIT, KRAS, MAPK2K1/2, MET, NRAS, PDGFRA, PIK3CA, PTPN11, RET, SOS1, and TP53. The majority of mutations were confirmed by Sanger sequencing. PIK3CA mutations were identified in 12/25 CCL (48%); paired normal breast tissue was tested in 21 cases and was negative for mutations in all but one case. In associated DCIS, 4/8 (50%) harbored PIK3CA mutations, while 3/9 IDC had mutations (33%, 2 PIK3CA, 1 AKT1). The mutation status of CCL and carcinomas was frequently discordant. Of 15 cases, only 6 demonstrated the same genotype in matched samples of CCL and carcinoma (5 wildtype, 1 PIK3CA H1047R). Interestingly, 5 patients had mutations in CCL with wildtype DCIS or IDC; 2 patients had different point mutations in CCL and carcinoma, including one patient with discordant mutant DCIS and wildtype IDC. Only 3 cases had wildtype CCL and mutated carcinoma. The nearly 50% PIK3CA mutation prevalence in CCL is greater than reported in most studies of invasive breast cancer. Further, CCL and carcinoma were frequently discordant for PIK3CA/AKT1 mutation status; most commonly the CCL harbored a PIK3CA mutation, while the associated carcinoma was wildtype. Although these findings need validation in a larger study, they raise interesting questions as to the role of PIK3CA/AKT pathway in breast carcinogenesis, and as to the biologic/precursor potential of CCL. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-06-04.

P2-14-10: Are There Variations in Invasive Tumour Characteristics between Different Ethnic Groups?

Abstract Introduction: Studies have shown that ethnic minorities with breast cancer are more likely to present at a younger age and with more aggressive tumours. The aim of this study was to examine the variation in tumour characteristics and surgical outcomes in different ethnic groups in our breast unit over a 12-month period. Methods: A retrospective study was performed on all patients with a new diagnosis of breast cancer, either screen-detected or symptomatic, between January to December 2009. Using our Trust databases, data on patient demographics, tumour characteristics, and ethnicity were collected. Where ethnicity was not documented, patients were contacted by telephone to complete the database. Those unable to be contacted were excluded from the study. Other exclusion criteria include those with recurrent ipsilateral breast cancer. Results: A total of 270 patients (265 females) were included in our study, of which 235 (87%) had invasive cancers (ductal carcinoma, lobular carcinoma, tubular carcinoma, mucinous carcinoma, cribriform carcinoma, papillary carcinoma, sarcoma) and the remaining 35 patients (13%) had non-invasive cancers (ductal carcinoma in-situ, lobular carcinoma in-situ, papilloma, columnar cell hyperplasia). We were unable to contact 23 (8.5%) patients to ascertain their ethnicity, and therefore these have been excluded from our results. Table 1. Tumour characteristics and surgical intervention in patients with invasive breast cancer in 2009 Conclusion: We found that the age of breast cancer presentation was lowest in Black and Asian patients (mean age 52 years and 54 years, respectively), compared to White (mean age 59 years). Furthermore, compared to white patients, tumours in Asian patients were larger (62.5% vs 47.2%), of higher grade (83.3% vs 75.2%), more likely to be ER negative (16.7% vs 12.4%), and tended to be lymph node positive (41.7% vs 34.2%). These may explain the higher mastectomy rate in Asian patients (n=12, 50%). The reason for the younger presentation age in the ethnic Asian group is unclear. However, it is possible that their cancer may have different tumour biology. Other studies have suggested reasons such as birth cohort effect and obesity. Reflecting the United Kingdom's population the majority of patients that present to our breast unit are White and the number of Asian patients remains small. An increase in the sample size may strengthen our results. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-10.

P5-11-13: Rates of Upgrade to Malignancy for 271 Cases of Atypical Columnar Cell Hyperplasia Diagnosed by Breast Core Biopsy.

Abstract Purpose: Atypical columnar cell hyperplasia (ACCH) is a borderline lesion that might represent an early stage in the development of certain low-grade carcinomas in situ (CIS) and invasive cancers. There are no guidelines on its management. Our objectives were to determine the upgrade to malignancy rate and identify a subpopulation of patients that might undergo just mammographic surveillance. Methods: We retrospectively reviewed the data for 271 ACCH cases among 5555 breast core biopsies obtained over a 7-year period (Jan. 2003 — Jan. 2010). We collated clinical data (age, history of cancer, menopausal status), radiological data (lesion type, size, Bi-Rads category), technical data (number of biopsies, needle gauge, excision quality) and histological data and sought correlations between these factors and upgrade rate. Results: The 271 ACCH comprised 128 cases of pure ACCH, 135 cases of ACCH + atypical ductal hyperplasia, and 8 cases of ACCH + atypical lobular hyperplasia. Overall, 184 patients underwent surgery and 46 mammographic surveillance. Surgery detected 34 cases of malignancy (23 CIS, 7 invasive cancers, and 4 mixed cases) giving a 15% upgrade rate. Quality of excision was the only factor associated with under-diagnosis. Conclusion: The presence of ACCH at biopsy warrants surgery. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-11-13.

Abstract P3-09-06: microRNA Signature of Columnar Cell Hyperplasia from Patients with High Risk of Breast Cancer

Abstract Background: Columnar cell hyperplasia (CCH) is considered to originate in normal terminal duct lobular units (TDLUs) and is potentially the first histologically identifiable alteration in the development of breast cancer. In order to detect early pathological changes in breast tissue, which could reveal the underlying mechanism to cancer progression, we investigated the microRNA (miRNA) expression profile in TDLUs and CCH. Material and Methods: Epithelial cells and surrounding stroma of TDLUs and CCH from formalin-fixed paraffin embedded tissue (FFPE) from patients with high risk of developing breast cancer were laser capture microdissected and RNA was extracted. MiRNA expression profiles were obtained using a qRT-PCR-based array analyzing 667 human miRNAs. Results: Increased levels of ERα were present in the epithelial cells of CCH as previously reported. Immunohistochemical staining for the stromal activation marker smooth muscle actin (SMA) was negative in fibroblasts surrounding both TDLUs and CCH, suggesting lack of major activation of the stroma. Interestingly, array analysis revealed changes in miRNA expression pattern in both epithelial and stromal compartments. Correlation analyses of the array results indicated a high reproducibility (r2:0.82-0.94) supporting stable miRNA profiles in TDLUa and CCH. MiRNA array analysis of paired samples from specimens with both TDLUs and CCH resulted in significant (P&amp;lt;0.05) decreased levels of 15 miRNAs in epithelial cells of CCH and downregulation of 18 miRNAs in the stroma. Examples of altered miRNAs in the epithelial cells are miR-532-3p, miR-886-3p, let-7c, miR-491-5p, miR-365, and example miRNAs in the stroma are miR-195, miR-99a, miR-224, miR-19b, miR-423-5p. Further validation of a selection of miRNAs in a patient material using in situ hybridization is currently being performed to verify the array results. Discussion: This data will potentially link these miRNAs to the development of TDLUs towards CCH and possibly lead to the discovery of new markers for precancerous conditions and potentially new therapeutic targets. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-09-06.

Lack of RUNX3 inactivation in columnar cell lesions of breast

Ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) exhibit frequent RUNX3 inactivation by promoter hypermethylation and protein mislocalization. The aim of this study was to analyse columnar cell lesions (CCLs) to further characterize RUNX3 involvement in breast carcinogenesis. RUNX3 expression and methylation was analysed by immunohistochemistry and methylation-specific polymerase chain reaction (PCR), respectively, in 75 CCLs. Our previously reported DCIS and IDC data were also included. Consistent with terminal duct lobular units (TDLUs) (73 of 75, 97%), active nuclear RUNX3 protein was observed in 73 of 75 (97%) CCLs [columnar cell change, 46 of 48 (96%); columnar cell hyperplasia, 12 of 12 (100%) and flat epithelial atypia, 15 of 15 (100%). In contrast to matched TDLUs from cancer specimens [four of 40 (10%)] and CCLs, significantly inactivated RUNX3 expression was detected in DCIS [17 of 20 (85%)] and IDC [18 of 20 (90%)] (all P < 0.001). RUNX3 methylation was more frequent in DCIS [15 of 20 (75%)] and IDC [16 of 20 (80%)] than CCLs [(none of 20 (0%)] and matched TDLUs [one of 10 (10%)] from cancer patients (all P < 0.001). RUNX3 inactivation occurs specifically in DCIS and IDC cells. In addition, RUNX3 inactivation may not be a common association between CCLs and breast carcinomas.