Columnar Cell Lesions Research Articles

Mucinous precursor lesions of mucinous carcinoma in breast: Incidence and histopathologic features

Objectives Columnar cell lesion (CCL), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) may be premalignant lesion of mammary invasive carcinoma. A few recent investigators reported that the precursor lesions exhibited mucin production and they might be potential precursor lesion for mucinous carcinoma (mCA). This study aims to investigate the incidence and histopathologic characteristics of mucinous precursor lesions, including mucinous DCIS (mDCIS) and mucinous CCL (mCCL). Methods We retrospectively analyzed invasive carcinomas with mucin. Cases were grouped into three subgroups: pure mCA, mixed mCA, and invasive carcinoma of no special type with mucin production (IC of NST-m). Precursor lesions were evaluated with PAS and alcian blue staining. Results Total 27 cases of invasive carcinoma with mucin were analysed and classified as 18 pure mCA, 7 mixed mCA, and 2 IC of NST-m. mDCISs were found in 12 pure mCA, 4 mixed mCA and 2 IC of NST-m. mCCLs were found in 7 pure mCA and 2 mixed mCA. Majority of mucin was identified in both cytoplasm and ductal lumen, while some tumors exhibited only cytoplasmic mucin. We also observed three patterns of mDCIS classifiable by location of mucin and architecture of tumor cells. Conclusions Cytoplasmic mucin suggested that mucinous feature of precursor lesions in the vicinity of mCA might not be a passive morphologic finding but be involved in development of mCA.

Columnar cell lesions of the breast: radiological features and histological correlation

This study aimed at investigating the characteristic imaging findings of the columnar cell lesions (CCLs) of the breast via mammography (MG), ultrasonography (US), and magnetic resonance imaging (MRI). The MG, US and MRI findings of 72 patients with histopathological diagnosis of CCLs were retrospectively evaluated. Histopathologically, the CCLs were divided into those with and without atypia; the radiological findings of these two groups were compared with a Chi-square test. Sixty-nine patients underwent stereotaxic biopsy (MG-guided in 50 patients and US-guided in 19 patients) and 3 patients underwent US-guided core needle biopsy; all of these patients were diagnosed with CCLs based on a histological examination. The evaluation of the CCLs in patients that underwent MG-guided stereotaxic biopsy revealed that the most common type of microcalcifications were amorphous-indistinct (52%, n= 26/50) and the most common microcalcification distribution pattern was clustered type (76%, n= 38/50). The ratio of CCLs with atypia was similar in patients with high-risk microcalcifications and in those with benign or intermediate-risk microcalcifications (OR: 1.13, 95% CI: 0.573-2.227, p: 0.475). On the other hand, those patients who underwent US-guided biopsies for the evaluation of CCLs had similar proportions of cystic or solid lesions, posterior acoustic shadowing and contour irregularities whether or not they had atypia (p: 0.584, 0.075, 0.187, respectively). Patients with atypia had a higher number of lesions greater than 1 cm via US as compared to those without atypia, but this difference was not statistically significant (p: 0.06). MRI findings were also similar in patients with and without atypia. MG revealed that clustered distribution patterns and amorphous- indistinct type microcalcifications were more commonly seen in patients with CCLs; however, there was no significant relationship between US or MRI findings and CCLs. In addition, the MG, US and MRI findings were similar in patients with CCLs that did or did not have histopathological characteristics of atypia.

Histopathological findings obtained from reduction mammoplasty specimens.

Reduction mammoplasty is a common surgical procedure. We report the incidence of nonproliferative and proliferative breast lesions in breast reduction specimens from a single institution over a 6-year period. The histopathology reports of all patients were analyzed. The clinical and histopathological findings of the patients were recorded. Between 2004 and 2010, 106 patients underwent breast reduction. Fifty-six patients (52.8%) had proliferative breast lesions, 84 patients (79.2%) had nonproliferative lesions, 8 patients (7.5%) had columnar cell lesions without atypia, 61 patients (57.5%) had columnar cell lesions with atypia, 5 patients (4.7%) had atypical ductal hyperplasia, and 6 patients (5.6%) had lobular carcinoma in situ. No invasive breast cancer was identified. In Turkey, there is limited evidence regarding the role of histopathological analysis in reduction mammoplasty. Moreover, none of the previous studies determined columnar cell lesion rates in reduction mammoplasty patients. The detection of significantly elevated columnar cell lesions, with or without atypia, especially in patients under the age of 40, increases the importance of screening tests, especially in Turkey, which has a high incidence of breast cancer in early ages, and addresses the need to starting screening tests early in these patients.

Histopathological Review of Male Breast Cancer Cases

Objective: Male breast cancer (MBC) accounts for less than 1% of all breast cancer diagnoses and all cancer cases in men. Methods: We included 33 MBC cases and analyzed histopathological features and survival data. Results: The mean age was 63.5, mean tumor diameter was 3 cm. Central quadrants (69.2%) was most common localization, invasive ductal carcinoma (75.8%) was most common histological subtype. Most of the cases (78.6%) were grade 2. Nipple involvement was noted in 9, tumor necrosis in 9, perineural invasion in 15, dermal lymphatic emboli in 10 cases. Nearly half of the cases (45.5%) showed lymph node metastasis. There was statistically significant relation between lymph node metastasis and stromal lymphocyte response, tumor necrosis (p=0.008, p=0.013) also between grade and dermal lymphatic emboli (p=0.04). Non-tumoral parenchymal findings were columnar cell lesions (CCL), (n: 5) and gynaecomastia (n: 3). Majority of the cases showed estrogen receptor (90.9%) and progesterone receptor (77.2%) positivity. Overall survival analysis showed significant results between grade (p=0.008), lymph node metastasis (p=0.03), dermal lymphatic tumor emboli (p=0.02), nipple involvement (p=0.02) and survival. Conclusions: Our results showed good correlation with literature data in terms of histopathological features and prognostic factors. Confidential data about etiological and prognostic factors will be collected through these reports showing institutional experiences. The significance of CCL in MBC etiology, the impact of intratumoral stromal lymphocyte response, hormone receptor-HER2 status on survival should be clarified in larger series

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.

Frequent phosphatidylinositol-3-kinase mutations in proliferative breast lesions

The phosphatidylinositol-3-kinase pathway is one of the most commonly altered molecular pathways in invasive breast carcinoma, with phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutations in 25% of invasive carcinomas. Ductal carcinoma in situ (DCIS), benign papillomas, and small numbers of columnar cell lesions harbor an analogous spectrum of PIK3CA and AKT1 mutations, yet there is little data on usual ductal hyperplasia and atypical ductal and lobular neoplasias. We screened 192 formalin-fixed paraffin-embedded breast lesions from 75 patients for point mutations using a multiplexed panel encompassing 643 point mutations across 53 genes, including 58 PIK3CA substitutions. PIK3CA point mutations were identified in 31/62 (50%) proliferative lesions (usual ductal hyperplasia and columnar cell change), 10/14 (71%) atypical hyperplasias (atypical ductal hyperplasia and flat epithelial atypia), 7/16 (44%) lobular neoplasias (atypical lobular hyperplasia and lobular carcinoma in situ), 10/21 (48%) DCIS, and 13/37 (35%) invasive carcinomas. In genotyping multiple lesions of different stage from the same patient/specimen, we found considerable heterogeneity; most notably, in 12 specimens the proliferative lesion was PIK3CA mutant but the concurrent carcinoma was wild type. In 11 additional specimens, proliferative epithelium and cancer contained different point mutations. The frequently discordant genotypes of usual ductal hyperplasia/columnar cell change and concurrent carcinoma support a role for PIK3CA-activating point mutations in breast epithelial proliferation, perhaps more so than transformation. Further, these data suggest that proliferative breast lesions are heterogeneous and may represent non-obligate precursors of invasive carcinoma.

Analysis of gene copy number alterations by multiplex ligation-dependent probe amplification in columnar cell lesions of the breast

Columnar cell lesions (CCLs) are possible precursors of breast cancer, but little is known about the role of breast cancer-related genes in the progression of CCL to invasive breast cancer. Gene copy numbers of 17 breast cancer-related genes were analyzed using Multiplex Ligation-dependent Probe Amplification (MLPA) in CCL (N = 28), ductal carcinoma in situ (DCIS) grade I likely originating from CCL (N = 5), and paired CCL (N = 14/28) with DCIS (N = 7) and/or invasive carcinoma (N = 13). The genes included were BIRC5, C11orf30, CCND1, CCNE1, CDH1, CPD, EGFR, ERBB2, ESR1, FGFR1, IKBKB, MAPT, MED1, MTDH, MYC, TOP2A and TRAF4. No high level gene amplifications were observed in CCL, but copy number gains were encountered for the C11orf30 (3/28), MYC, CPD, MTDH (2/28), and CCND1, CCNE1, ESR1 and TOP2A genes (1/28). In addition, CDH1 showed loss in 2/28 and TOP2A in 1/28 cases. CCLs with or without atypia exhibited comparable numbers of copy number changes (p = 0.312). Overall, the frequency of gene copy number changes increased from CCL towards DCIS and invasive carcinoma (p = 0.004). Also in the cases with synchronous lesions, the CCLs exhibited fewer copy number changes than the DCIS/invasive carcinomas. CCLs carry copy number changes of several known breast cancer-related genes, thereby substantiating their role in breast carcinogenesis. Among them, CCND1 and ESR1 copy number gains and CDH1 copy number losses are of particular interest. Since the copy number changes observed were more prevalent in DCIS and invasive carcinoma than in CCL, the corresponding gene alterations may represent rather late occurring events in low nuclear grade breast carcinogenesis.

Do columnar cell lesions exist in the male breast?

In females, columnar cell lesions (CCLs) have been recognized as putative precursor lesions of low-grade breast cancer, but their role in male breast carcinogenesis is as yet unclear. We reviewed surgical resections from males with breast cancer (n=89), gynaecomastia (n=20) and normal breast specimens from autopsies (n=5) for the presence of CCL. In addition, we performed immunohistochemistry for cytokeratin 5/6 (CK5/6), CK14 and oestrogen receptor alpha (ER). In 19 of 89 resections (two DCIS cases and 17 invasive carcinoma), some individual ducts were found to contain cells with snouts on the luminal border but lacking further typical columnar cell lesion features. We mainly found three-layered ductal epithelium, characteristic for gynaecomastia and confirmed by immunohistochemistry. Moreover, we found a few ducts in male breast cancer sections that were clonally negative for basal cytokeratins. We found no lesions with convincing CCL morphology at the periphery of invasive male breast cancers, in gynaecomastia or in normal male breast specimens. Although we cannot completely exclude the existence of CCLs in the male breast, these lesions seem to be very uncommon and are therefore unlikely to play a major role in male breast carcinogenesis.

Update on WHO breast classification -2 years on

The 4th edition of the WHO classification of Tumours of the Breast was published in 2012, as a separate volume from the gynae book. The editors and the international panel of breast pathologists have attempted to produce a consensus document that will help to standardize classification worldwide. In addition to microscopic criteria that define tumour types, there is incorporation of relevant updated molecular information. Many of the diagnostic problems in clinical practice reside in the B3 category, which comprises a heterogeneous group of proliferations that include atypical ductal hyperplasia (ADH), lobular neoplasia (ALH/LCIS), columnar cell lesions (CCL) and flat epithelial atypia (FEA), radial scar (RS/CSL), phyllodes tumours, papillary lesions, mucinous lesions and spindle cell proliferations. In clinical practice, the rate of B3-biopsies ranges from 3-10%. In this lecture, I will cover some of the diagnostic issues that have been discussed since the publication of the 4th edition. They centre on this group of lesions which form a significant component of consult practice throughput the world, suggesting that the diagnostic criteria and classification systems are still far from robust. The 4th edition of the WHO classification of Tumours of the Breast was published in 2012, as a separate volume from the gynae book. The editors and the international panel of breast pathologists have attempted to produce a consensus document that will help to standardize classification worldwide. In addition to microscopic criteria that define tumour types, there is incorporation of relevant updated molecular information. Many of the diagnostic problems in clinical practice reside in the B3 category, which comprises a heterogeneous group of proliferations that include atypical ductal hyperplasia (ADH), lobular neoplasia (ALH/LCIS), columnar cell lesions (CCL) and flat epithelial atypia (FEA), radial scar (RS/CSL), phyllodes tumours, papillary lesions, mucinous lesions and spindle cell proliferations. In clinical practice, the rate of B3-biopsies ranges from 3-10%. In this lecture, I will cover some of the diagnostic issues that have been discussed since the publication of the 4th edition. They centre on this group of lesions which form a significant component of consult practice throughput the world, suggesting that the diagnostic criteria and classification systems are still far from robust.

乳腺線維腺腫内に発生した非浸潤性乳管癌の1例

A 70-year-old woman visited our breast clinic, because a right breast mass had been noted in enhanced computed tomography (CT) before surgery for intrahepatic bile duct cancer. A tumor was located in the D region of the right breast. It was spiculated and comparatively elastic. Mammography revealed a tumor mass with coarse calcification in the middle outer quadrant of the right breast. Initially, a fibroadenoma was suspected. Ultrasonography revealed a tumor in the CD region of the right breast that was 41×41×16 mm in size, oval shaped, and smooth-surfaced, with a heterogeneous low-echoic level inside, no interruption of the border of the mammary gland, with fine or small and coarse calcification, and a small amount of flow. Magnetic resonance imaging (MRI) also led to an initial speculation that it was fibroadenoma. Core needle biopsy resulted in a diagnosis of ductal carcinoma in situ (DCIS). Right breast partial resection was performed. Pathological findings revealed an 11 mm×8 mm DCIS in the fibroadenoma, around which usual ductal hyperplasia, columnar cell lesions, flat epithelial atypia, atypical ductal hyperplasia, papillomatosis, and sclerosing adenosis were observed.

Abstract P1-02-11: Flat epithelial atypia on breast core biopsy: Is excision warranted?

Abstract Columnar cell lesions of the breast are common findings in core biopsies for mammographically indeterminate calcifications. Atypical columnar cell lesions, also referred to as flat epithelial atypia (FEA), confer a mildly increased risk of subsequent carcinoma and are often co-localized with other patterns of atypia. The management of FEA diagnosed on core biopsy remains controversial with studies reporting carcinoma on excisional biopsy in 13 to 67% of cases. We report the frequency of carcinoma in excision specimens after a diagnosis of FEA on core biopsy over a nine year period at Carolinas Medical Center. Cases were identified from our files for the period from January 2004 through October 2012. Core biopsies with FEA as the most “advanced” lesion were included. Exclusion criteria included another pattern of atypia, carcinoma in situ, or invasive carcinoma in ipsilateral core biopsies performed concurrently or within four months of the core biopsy with FEA alone. The pathology reports for excision specimens following a core biopsy with FEA alone were retrieved. For each core biopsy with pure FEA, the histologic and mammographic findings were correlated. A total of 116 cases with a diagnosis of FEA on core biopsy were identified. Two (2) cases were ultrasound core biopsies, 1 was MRI-guided, and the remaining 113 cases were stereotactic core biopsies performed for calcifications. FEA was the most advanced lesion in 53 cases (46%), corresponding to 55 core biopsies. In the 63 cases with FEA and a more advanced lesion, 34 (29%) contained atypical ductal hyperplasia, 6 (5%) atypical lobular hyperplasia, 4 (3%) atypical ductal and lobular hyperplasia, 11 (10%) ductal carcinoma in situ, 2 (2%) lobular carcinoma in situ, and 6 (5%) invasive carcinoma. Of the 55 core biopsies with FEA alone, excision pathology reports were unavailable for 11 cases, and an ipsilateral core biopsy contained a more advanced lesion in 6 cases. Of the 38 remaining cases, 4 excision specimens (11%) contained carcinoma and 8 specimens (21%) contained another, higher risk pattern of atypia (atypical ductal hyperplasia or atypical lobular hyperplasia). Excision results are summarized in the table below: 10 (26%) contained no residual atypia, 16 (42%) residual FEA, 7 (18%) atypical ductal hyperplasia, 1 (3%) atypical lobular hyperplasia, 3 (8%) ductal carcinoma in situ, and 1 (3%) invasive carcinoma. Excision Findings after Pure FEA on Core BiopsyTotalNo AtypiaFEAADHALHDCISInvasive3810 (26%)16 (42%)7 (18%)1 (3%)3 (8%)1 (3%) The data from a nine year period at our institution demonstrate an 11% upgrade rate to carcinoma for patients with a diagnosis of FEA on core biopsy. The higher risk patterns of atypia (atypical ductal hyperplasia or atypical lobular hyperplasia) found in 21% of cases also impact risk stratification and future clinical and radiographic follow-up. In total, future clinical management was altered in 32% of patients based on excision specimen results. The findings support performing an excisional biopsy for a core biopsy containing FEA. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-02-11.

Activation of mTORC1 in Collecting Ducts Causes Hyperkalemia

Mutation of TSC (encoding tuberous sclerosis complex protein) and activation of mammalian target of rapamycin (mTOR) have been implicated in the pathogenesis of several renal diseases, such as diabetic nephropathy and polycystic kidney disease. However, the role of mTOR in renal potassium excretion and hyperkalemia is not known. We showed that mice with collecting-duct (CD)-specific ablation of TSC1 (CDTsc1KO) had greater mTOR complex 1 (mTORC1) activation in the CD and demonstrated features of pseudohypoaldosteronism, including hyperkalemia, hyperaldosteronism, and metabolic acidosis. mTORC1 activation caused endoplasmic reticulum stress, columnar cell lesions, and dedifferentiation of CD cells with loss of aquaporin-2 and epithelial-mesenchymal transition-like phenotypes. Of note, mTORC1 activation also reduced the expression of serum- and glucocorticoid-inducible kinase 1, a crucial regulator of potassium homeostasis in the kidney, and decreased the expression and/or activity of epithelial sodium channel-α, renal outer medullary potassium channel, and Na(+), K(+)-ATPase in the CD, which probably contributed to the aldosterone resistance and hyperkalemia in these mice. Rapamycin restored these phenotypic changes. Overall, this study identifies a novel function of mTORC1 in regulating potassium homeostasis and demonstrates that loss of TSC1 and activation of mTORC1 results in dedifferentiation and dysfunction of the CD and causes hyperkalemia. The CDTsc1KO mice provide a novel model for hyperkalemia induced exclusively by dysfunction of the CD.

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.

Columnar cell-like changes in the male breast

AimsColumnar cell lesions are known as a link between normal breast and low grade neoplastic lesions in female, but have not been established in the male breast. This study evaluated...

Pseudo-micropapillary structures associated with columnar cell lesions of the breast are an artifact due to traumatic epithelial detachment: a potential pitfall which can lead to overtreatment

Dear Editor, Columnar cell lesions (CCLs) of the breast including flat epithelial atypia (FEA) are believed to be nonobligatory precursors of a low-nuclear-grade breast neoplasia family [1]. They are detected increasingly in needle core biopsies because of the presence of microcalcifications observed on screening mammography. Here, we report a hitherto undescribed artifact associated with CCLs of the breast, which superficially resembles micropapillary atypical ductal hyperplasia (ADH) or low-grade ductal carcinoma in situ (DCIS). The complexity of this artifact varies widely from a simple fold to a complex labyrinthine-like structure. If the latter is confused with genuine micropapillary structures or Roman bridges, overtreatment can occur because management of patients differs between pure CCLs and those associated with ADH/low-grade DCIS, especially when found in needle core biopsies. We have recently observed two cases of CCL of the breast that showed complex pseudo-micropapillary structures protruding into the duct lumen. Based on histopathological and immunohistochemical findings, we infer that these structures are not a true micropapillary overgrowth but an artifact, which originates from folding and adhesion of epithelial sheets detached from CCLs. The first case concerns a 49-year-old Japanese woman whose screening mammography revealed microcalcifications in the left breast. Vacuum-assisted needle core biopsy (VAB) was performed because the microcalcifications varied in size and shape and were localized to the upper half of the breast in a segmental fashion. The VAB was composed of 12 fragments of breast tissue. Four fragments contained CCLs; variably distended ductules were lined by columnar epithelial cells with apical cytoplasmic snouts (Fig. 1a–c). In the lumina of some dilated ductules, racetracks were seen or ribbon-like bridges continuous with the epithelial lining of CCL. These pseudo-micropapillary structures lacked fibrovascular cores and contained two epithelial layers. The cells were similar to luminal cells of CCL (Fig. 1c). Immunohistochemical staining with cytokeratin 5/6 demonstrated a few myoepithelial cells attached to the basal S. Ichihara (*) : S. Moritani :M. Hasegawa Department of Pathology, Nagoya Medical Center, 4-1-1 Sannomaru Naka-ku Nagoya, 460-0001 Aichi, Japan e-mail: shu-kkr@umin.ac.jp

Borderline Atypical Ductal Hyperplasia/Low-grade Ductal Carcinoma In Situ on Breast Needle Core Biopsy Should Be Managed Conservatively

The differential diagnosis of low-nuclear grade intraductal epithelial proliferations of the breast includes atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). This distinction can be difficult on core needle biopsy (CNB) but can have significant clinical ramifications. We examined the clinical course of patients diagnosed on CNB with borderline ADH/DCIS lesions [marked ADH (MADH)] at our institution. A total of 74 patients were diagnosed with MADH on CNB and underwent an excisional biopsy (EB). The majority of these CNBs reviewed at outside hospitals had been classified as DCIS. Twenty patients (27%) had benign findings or lobular neoplasia in their EB, 18 (24%) had ADH, 33 (45%) had DCIS, and 3 (4%) had DCIS and invasive ductal carcinoma (IDC). Among the 38 patients who were not diagnosed with DCIS or IDC on EB, no patient underwent further surgery or radiation postoperatively. Thirty-seven of these 38 patients had no recurrences, whereas 1 patient developed a "recurrence" that on our review was likely residual localized MADH. The mean follow-up for these patients was 54 months. Of the 36 patients diagnosed with DCIS or IDC on EB, <20% required mastectomy. On review, MADH involving an intermediate-sized duct on CNB and the amount of residual lesion on imaging was significantly associated with DCIS or IDC on EB. Conversely, MADH involving columnar cell lesions and the presence of calcification on CNB were significantly associated with benign pathology on EB. In conclusion, our study provides preliminary data that justify a conservative approach to borderline ADH/DCIS lesions on CNB: that is, diagnose as MADH and treat by conservative excision.

Changed lineage composition is an early event in breast carcinogenesis.

The epithelium compartment of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal epithelial cells surrounded by contractile myoepithelial cells. The co-ordinated development of these two cell types, and maintenance of their relative proportions, is fundamentally important for normal breast morphogenesis. Changes in cell type composition is one of the hallmark features of breast cancer progression, and the vast majority of breast tumors are comprised of luminal cells only, with a complete absence of myoepithelial cells. Despite this striking alteration in relative proportions of luminal and myoepithelial cells in invasive breast cancers compared with normal breast tissue, the steps in this dramatic change in cellular composition remain poorly characterised, nor is it known whether loss of myoepithelial cells is an early event in carcinogenesis. In a panel of breast tissues, we quantitated the proportion of luminal cells relative to the surrounding myoepithelial cell layer in a panel of normal and pre-invasive breast tissue samples, including lesions with proliferative disease without atypia (PDWA), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and DCIS, and correlated these findings with proliferation in the same lesions. The study findings showed that changes in lineage composition correlate with increased proliferation, and are one of the earliest events in breast carcinogenesis. Therefore not only are myoepithelial cells important in distinguishing between invasive and non-invasive tumors, their relative proportion compared with luminal cell numbers may provide a new potential indicator of which premalignant lesions are at higher risk of progression to invasive disease.

Diagnostic challenges in breast pathology

The use of needle core biopsies to evaluate abnormalities identified on breast screening is now well established. This together with an incomplete knowledge of the natural history of many disease processes has led to diagnostic challenges in the accurate classification of breast disease. Many of the diagnostic problems reside in the B3 category, which comprises a heterogeneous group of proliferations that include atypical ductal hyperplasia (ADH), lobular neoplasia (ALH/LCIS), columnar cell lesions (CCL) and flat epithelial atypia (FEA), radial scar (RS/CSL), phyllodes tumours, papillary lesions, mucinous lesions and spindle cell proliferations. In clinical practice, the rate of B3-biopsies ranges from 3% to 10%. In this lecture, I will cover some of the diagnostic issues and the changing classification related to papillary lesions of the breast and columnar cell lesions with and without atypia. These lesions form a significant component of consult practice throughout the world, suggesting that the diagnostic criteria and classification systems are far from robust.

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.

Abstract MS2-2: Breast Density: Clinical Implications

Abstract Potential clinical applications of mammographic density include: 1) the prediction of outcome of breast disease, 2) mammographic screening, 3) research and practice of cancer prevention, and 4) improved prediction of risk in individuals. 1) Breast cancer characteristics and clinical outcomes. Extensive percent mammographic density (PMD) is associated with increased risks for the development of most of the histological non-obligate precursors of breast cancer, including ductal carcinoma in situ (DCIS), atypical hyperplasia, hyperplasia without atypia, and columnar cell lesions (CLLs). PMD is associated with an increased risk of both ER+ and ER− tumors, and with larger tumors of higher histological grade. Risk of contralateral second breast cancer is also increased by extensive PMD. However, among women with breast cancer, risk of death from the disease does not appear to be increased by PMD. 2) Mammographic screening. Women with extensive PMD are both at higher risk of breast cancer and at greater risk that cancer will not be detected by mammography. This heterogeneity is not currently recognized in the design of screening programs. Women with extensive PMD, might benefit from screening more often than once every 2 to 3 years and with modalities such as MR or UST in addition to mammography. Conversely, for women with radiolucent breast tissue and a negative screening mammogram, in whom risk is lower and detection easier, re-screening less frequently than every 2 to 3 years with mammography might be safe. Research into these issues is required. 3) Breast cancer prevention trials. Unlike most other risk factors for breast cancer, PMD can be changed), suggesting that it might be used as a surrogate marker in clinical trials of breast cancer prevention. Clinical trials of breast cancer prevention require large numbers of subjects and long periods of observation and thus are expensive. Smaller, shorter, and less expensive trials of prevention strategies would be possible if there were a surrogate marker that allow the identification of interventions that would reduce breast cancer incidence. To be used as a surrogate for breast cancer, a biomarker such as PMD should meet the following criteria: (a) the marker should be associated with risk of breast cancer, (b) the marker should be changed by the intervention, and (c) the change in the marker should mediate the effect of the intervention on breast cancer risk. The extent to which these criteria can currently be met will be discussed. 4) Improved risk prediction. PMD is inversely associated with age, while breast cancer incidence increases with age. We used data from 3250 healthy women aged 15–80 to estimate cumulative breast density (CBD) in the population, which increases with age, and compared this with age-specific incidence of breast cancer in Canada. Log CBD and log breast cancer incidence had a linear association (r = 0.98; p = 6.0 E−9) that was unchanged by adjustment for log age (r = 0.97; p = 8.0 E−7). Log CBD alone was a better predictor of age-specific log breast cancer incidence (r2 = 0.97) than age alone (r2 = 0.88). The observed strong association between CBD and breast cancer incidence suggest that the factors responsible for CBD may be causally related to the age-specific incidence of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS2-2.