Tubular carcinoma of the breast and associated intra-epithelial lesions: a comparative study with invasive low-grade ductal carcinomas

Ductal intra-epithelial lesions of the breast are associated with invasive neoplasms and comprise a large spectrum of histological patterns. We have examined 23 cases of pure tubular carcinomas (TCs) of the breast and 53 cases of invasive ductal low-grade carcinomas to determine the relationship and distribution of intra-epithelial lesions, mainly of ductal in situ carcinoma type, but including also lobular intra-epithelial neoplasia (LIN) in both entities. Eleven cases of TC showed flat epithelial atypia (FEA) (47.8%), and, in 14 and 6 cases, micropapillary and cribriform low-grade ductal carcinoma in situ (DCIS) were present (60.7 and 26.1%, respectively). On the opposite, in ductal grade I invasive carcinomas, the most frequent architectural pattern was low-grade DCIS growing in arcades in 26 cases (49%). While absent in TCs, low-grade DCIS of solid type was found in five (9.4%) cases of ductal invasive carcinomas, where FEA were present in seven (13.2%) cases. LIN lesions were present in four (17.4%) cases of TC, whereas they represented 7.5%, as reported by Carstens et al. (Am J Clin Pathol 58:231–238, 1972), of cases of low-grade carcinomas. These results suggest that invasive pure TC and low-grade ductal carcinomas of the breast are different lesions, and support the fact that TC, of low histopathological grade, is a particular distinct tumoural entity.     

The significance of lobular neoplasia on needle core biopsy of the breast

The management of a core biopsy diagnosis of lobular neoplasia is controversial. Detailed radiological–pathological review of 47 patients with cores showing classical lobular neoplasia was performed (patients with pleomorphic lobular carcinoma in situ (LCIS) or associated risk lesions were considered separately). Immediate surgical excision in 25 patients showed invasive carcinoma in 7, ductal carcinoma in situ (DCIS) in 1 and pleomorphic LCIS in 1; radiological–pathological review showed that the core biopsy missed a mass in 5, missed calcification in 2 and that calcification appeared adequately sampled in 2. Nineteen patients had follow-up of at least 2 years. Four patients developed malignancy at the site of the core biopsy (invasive carcinoma in three, DCIS in one); one carcinoma was mammographically occult, one patient had dense original mammograms and two had calcifications apparently adequately sampled by the core. In conclusion, most carcinomas identified at the site of core biopsy showing lobular neoplasia were the result of the core missing the radiological lesion, emphasising the importance of multidisciplinary review and investigation of any discordance. Some carcinomas were found after apparently adequate core biopsy, raising the question of whether excision biopsy should be considered after all core biopsy diagnoses of lobular neoplasia.     

Chromosomal aberrations as detected by array comparative genomic hybridization in early low-grade intraepithelial neoplasias of the breast

Stacher E, Boldt V, Leibl S, Halbwedl I, Popper H H, Ullmann R, Tavassoli F A & Moinfar F
(2011) Histopathology 59 , 549–555 Chromosomal aberrations as detected by array comparative genomic hybridization in early low‐grade intraepithelial neoplasias of the breast Aims: Low‐grade flat ductal intraepithelial neoplasia (DIN1a, flat epithelial atypia) is one of the earliest morphologically recognizable neoplastic lesions of the breast. Frequently, it occurs concomitantly with lobular intraepithelial neoplasia (LIN). We aimed to elucidate chromosomal aberrations in these early neoplastic breast lesions with the use of array comparative genomic hybridization analysis. Methods and results: Laser capture microdissection of 12 archival formalin‐fixed, paraffin‐embedded specimens harbouring foci of both DIN1a and LIN was performed. All analysed cases of DIN1a and LIN showed chromosomal gains and losses. The aberration encountered most often was loss of 16q, noted in seven DIN1a (70% of those successfully examined) and 10 LIN (91%) cases. The next most common alteration was a gain on 1q, noted in four DIN1a (40%) and seven LIN (64%) cases. Conclusions: The results show concurrent chromosomal aberrations of 1q gains and 16q losses in several cases with coexisting LIN and DIN1a. These aberrations are known to be common in low‐grade invasive (ductal and lobular) carcinomas as well as in more advanced (conventional) types of low‐grade ductal intraepithelial neoplasia (DIN) (low‐grade ductal carcinoma in situ). Our results raise the possibility of similar molecular‐genetic pathways in coexisting LIN and low‐grade flat DIN.     

CD24 expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: an immunohistochemistry-based pilot study

CD24 is a small, heavily glycosylated cell surface protein, that is expressed in a large variety of solid tumors. It is considered to play an important role in tumor progression and metastasis. We aimed to evaluate CD24 expression in invasive ductal carcinomas (IDCa), ductal carcinoma in situ (DCIS) and non-tumorous breast tissues, and to investigate the relationship between histopathological parameters, estrogen and progesterone receptors, and c-erbB2 expressions. The study included 34 IDCa, 25 DCIS, and 13 non-tumorous breast tissues. All cases were reevaluated histopathologically, and immunohistochemistry was performed with monoclonal CD24 antibody. The results clearly demonstrated that CD24 expression, including membranous and cytoplasmic staining, was significantly higher in DCIS and IDCa than in the non-tumorous breast (p=0.001, p=0.000, and p=0.035, p=0.000, respectively). Cytoplasmic staining was detected predominantly in neoplastic tissues and was significantly increased in high grade DCIS (p=0.013). In invasive carcinomas, although the level of membranous staining was significantly positively correlated with tumor grade (p=0.040), there was no such an association with the cytoplasmic level. However, it showed a trend towards pT (p=0.089). In conclusion, our results suggest that higher CD24 expression may be associated with malignant transformation and progression in breast cancer biology. Furthermore, higher membranous expression and, in particular, cytoplasmic staining seem to predict malignant transformation, and different patterns of CD24 expression may be associated with different pathological features in breast tumors.     

In situ and invasive lobular neoplasia of the breast

Lobular neoplasia of the breast represents a group of related malignancies with clinical implications ranging from risk lesions [atypical lobular hyperplasia and lobular carcinoma in situ (LCIS)] through to aggressive invasive lesions, notably invasive pleomorphic lobular carcinoma. The diversity in lobular carcinoma is evident at the morphological level, at the molecular marker level and in cytogenetic profiles. Research in these areas is already changing the face of the disease group, for example suggesting that some lobular and ductal carcinomas are closely related and even that one of the lobular group, the tubulo-lobular carcinomas, should, in fact, be regarded as a ductal cancer. More research is required to understand the long-term pathogenic implications of a diagnosis of in situ lobular neoplasia, particularly pleomorphic LCIS , and to understand the genetics behind the well-recognized high risk of bilateral disease. For invasive carcinoma, molecular studies will allow refinement of therapy and the possibility of novel targeted therapies, for example directed against fibroblast growth factor receptor 1.     

Lobular in situ neoplasia and columnar cell lesions: diagnosis in breast core biopsies and implications for management

Histopathologists are encountering intra-lobular epithelial proliferations more frequently in core biopsies taken from lesions identified in mammographic breast screening programmes. In particular, columnar cell lesions are increasingly being seen in core biopsies taken for the histological assessment of mammographically detected microcalcifications. The morphological features of lobular neoplasia are relatively well known, but columnar cell lesions, particularly forms with atypical features, are less widely recognised. The biological and clinical significance of both of these intra-lobular processes is controversial, (1) as indicators of adjacent malignancy when encountered in core biopsy, (2) the relative risk conferred of development of subsequent malignancy, and (3) their precursor behaviour. For this reason, the optimal clinical management of these lesions, particularly when encountered on core biopsy, is unclear. This review provides an update on the histological diagnosis of lobular neoplasia and columnar cell lesions and outlines recent clinico-pathological and molecular findings with discussion on clinical management.     

Impact of immunohistochemical markers, CK5/6 and E-cadherin on diagnostic agreement in non-invasive proliferative breast lesions

Aims:  To assess the impact of cytokeratin (CK) 5/6 and E-cadherin immunohistochemistry on diagnostic agreement of non-invasive proliferative breast lesions.
Methods and results:  Twenty pathologists classified 105 cases of non-invasive proliferative breast lesions into 10 diagnostic categories. One haematoxylin and eosin (H&E) slide of each case was analysed on a first round and one H&E slide with corresponding CK5/6 and E-cadherin immunohistochemistry was analysed on a second round. Interobserver reproducibility for category-specific and management-specific lesions was measured on each round. CK5/6 and E-cadherin had little impact on diagnostic agreement, which remained moderate between the first and second rounds (overall κ coefficients of 0.47 and 0.53, respectively, P  = NS). Levels of agreement slightly improved for lesions with specific CK5/6 and E-cadherin immunoprofiles (usual ductal hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ , non-high-grade ductal carcinoma in situ ), but the differences observed were not statistically significant. However, diagnostic agreement improved when lesions were grouped according to their management category (overall κ coefficients of 0.58 and 0.66 in the first and second rounds, respectively).
Conclusions:  CK5/6 and E-cadherin immunohistochemistry has little impact on interobserver reproducibility for non-invasive breast lesions. Diagnostic agreement can, however, be improved by grouping lesions in management categories.     

Epithelial atypia in biopsies performed for microcalcifications. Practical considerations about 2,833 serially sectioned surgical biopsies with a long follow-up

This study analyzes the occurrence of epithelial atypia in 2,833 serially sectioned surgical breast biopsies (SB) performed for microcalcifications (median number of blocks per SB:26) and the occurrence of subsequent cancer after an initial diagnosis of epithelial atypia (median follow-up 160 months). Epithelial atypia (flat epithelial atypia, atypical ductal hyperplasia, and lobular neoplasia) were found in 971 SB, with and without a concomitant cancer in 301 (31%) and 670 (69%) SB, respectively. Thus, isolated epithelial atypia were found in 670 out of the 2,833 SB (23%). Concomitant cancers corresponded to ductal carcinomas in situ and micro-invasive (77%), invasive ductal carcinomas not otherwise specified (15%), invasive lobular carcinomas (4%), and tubular carcinomas (4%). Fifteen out of the 443 patients with isolated epithelial atypia developed a subsequent ipsilateral (n = 14) and contralateral (n = 1) invasive cancer. The high slide rating might explain the high percentages of epithelial atypia and concomitant cancers and the low percentage of subsequent cancer after a diagnosis of epithelial atypia as a single lesion. Epithelial atypia could be more a risk marker of concomitant than subsequent cancer.     

Atypical ductal hyperplasia on vacuum-assisted breast biopsy: suspicion for ductal carcinoma in situ can stratify patients at high risk for upgrade

We evaluated 97 cases of review-confirmed atypical ductal hyperplasia found on stereotactic vacuum-assisted breast biopsy of suspicious calcifications. The number and size of foci of atypical ductal hyperplasia and presence of a micropapillary component were noted. In addition, we recorded if a case was considered "atypical ductal hyperplasia suspicious for ductal carcinoma in situ" using specific qualitative criteria. The upgrade rate was 20.6% (20/97) for all cases and 48% (12/25) for cases suspicious for ductal carcinoma in situ. Suspicion for ductal carcinoma in situ was found to be a strong predictor of upgrade with an odds ratio of 7.4 (P = .0003). Suspicious cases with nuclear features bordering on intermediate nuclear grade had the highest upgrade rate of 75% (6/8). Cases with ≥ 3 foci had significantly higher upgrade rates (28%) than those with less than 3 foci (11%), but focal atypical ductal hyperplasia did upgrade (P = .04). In conclusion, qualitative features of atypical ductal hyperplasia on core biopsy such as suspicion for ductal carcinoma in situ may help stratify patients at the highest risk for upgrade.     

Discrepancies in the diagnosis of intraductal proliferative lesions of the breast and its management implications: results of a multinational survey

To measure discrepancies in diagnoses and recommendations impacting management of proliferative lesions of the breast, a questionnaire of five problem scenarios was distributed among over 300 practicing pathologists. Of the 230 respondents, 56.5% considered a partial cribriform proliferation within a duct adjacent to unequivocal ductal carcinoma in situ (DCIS) as atypical ductal hyperplasia (ADH), 37.7% of whom recommended reexcision if it were at a resection margin. Of the 43.5% who diagnosed the partially involved duct as DCIS, 28.0% would not recommend reexcision if the lesion were at a margin. When only five ducts had a partial cribriform proliferation, 35.7% considered it as DCIS, while if ≥20 ducts were so involved, this figure rose to 60.4%. When one duct with a complete cribriform pattern measured 0.5, 1.5, or 4 mm, a diagnosis of DCIS was made by 22.6, 31.3, and 94.8%, respectively. When multiple ducts with flat epithelial atypia were at a margin, 20.9% recommended reexcision. Much of these discrepancies arise from the artificial separation of ADH and low-grade DCIS and emphasize the need for combining these two under the umbrella designation of ductal intraepithelial neoplasia grade 1 (DIN 1) to diminish the impact of different terminologies applied to biologically similar lesions.     

Significance of flat epithelial atypia on mammotome core needle biopsy: Should it be excised?

The aim of this study was to determine the morphologic types, associations, and significance of flat epithelial atypia (FEA) with or without atypical ductal hyperplasia (ADH) in mammotome core needle biopsies. We evaluated the correlation of FEA in core biopsies with follow-up excision biopsies to predict the likelihood of upgrade to carcinoma. We also investigated the utility of Ki-67 in predicting which lesions were associated with carcinoma in the excisional biopsies. Core biopsies with a diagnosis of atypia were categorized as pure FEA, pure ADH, or both. The following parameters were recorded: indication for core biopsies, presence of microcalcifications, inflammation, and stromal changes. A total of 60 core biopsies from 56 patients were studied. Pure ADH, pure FEA, and concomitant FEA and ADH were seen in 13%, 23%, and 64% of core biopsies, respectively. The most common architectural pattern of FEA resembled blunt duct adenosis (52%), followed by cystically dilated ducts with secretions (38%) and apocrine features (10%). Chronic inflammation and stromal changes were noted in 29% and 36% of FEA, respectively. Excisional biopsies in 48 of 56 patients demonstrated ductal carcinoma in situ and/or invasive carcinoma in 10 patients (21%), lobular carcinoma in situ or atypical lobular hyperplasia in 5 (11%), residual ADH in 11 (23%), and no atypia in 24 patients (50%). Three (21%) of 14 pure FEA upgraded to ductal carcinoma in situ and/or invasive carcinoma on excisional biopsy. The staining for Ki-67 in FEA/ADH was similar regardless of whether they were upgraded to carcinoma or not. In summary, we found a strong association between FEA and ADH, which may reflect a biologic progression. Most FEAs have a low-power appearance of a well-circumscribed group of ducts. Chronic inflammation and stromal changes are present in a subset of cases. Flat epithelial atypia shows a risk of upgrade to carcinoma similar to that of ADH and, hence, should be recognized and warrants a follow-up excision.     

Lobular endocrine neoplasia in a fibroadenoma of the breast

Summary The authors report a case of lobular endocrine neoplasia within fibroadenoma of the breast. The main pathological differences to similar cases previously described are discussed.The histochemical and ultrastructural findings suggest that, in our case, the neoplasia may be a variant of lobular carcinoma in situ.     

Flat DIN 1 (flat epithelial atypia) on core needle biopsy: 63 cases identified retrospectively among 1,751 core biopsies performed over an 8-year period (1992–1999)

Uniform management of flat DIN 1 (flat epithelial atypia) on core needle biopsy (CNB) concerning surgical excision or clinical follow-up are lacking. In a retrospective review of 1,751 CNB over an 8-year period, we found 63 cases with flat DIN 1 as the most advanced lesion; follow-up was available in 55 cases. Of the 63 patients, 24 had a subsequent biopsy for 15 days to 10 years after the initial CNB, an infiltrating carcinoma was found in nine (14.3%) patients, seven (11.1%) in the ipsilateral, and two (3.2%) in the contralateral breast. Five underwent an excisional biopsy of the ipsilateral breast within less than 3 months of the initial CNB; none had either an invasive or intraepithelial carcinoma. Based on our findings, we consider flat DIN 1 a marker of slightly increased risk for subsequent development of invasive breast carcinoma. When flat DIN 1 is found on CNB as the most advanced lesion after mammographic correlation, an excisional biopsy is not mandatory; however, close follow-up is advised with repeat mammograms for early detection of any clinically occult carcinoma in the vicinity of flat DIN 1 that may have been missed by the CNB.     

Costimulatory molecule OX40/OX40L expression in ductal carcinoma in situ and invasive ductal carcinoma of breast: An immunohistochemistry-based pilot study

OX40, a membrane-bound member of the tumor-necrosis-factor-receptor (TNFR) superfamily, plays an important role in proliferation, survival and infiltration of activated T cells via binding to OX40L. Recent studies indicate that OX40/OX40L system mediates the adhesion and infiltration of adult T cell leukemia (ATL). Previously, we detected OX40 expression in breast carcinoma cell lines and tissues. The correlation of expression of OX40 and OX40L and clinical features in breast carcinogenesis, however, has not been well characterized. The expression of OX40 and OX40L in 107 invasive ductal carcinomas (IDCa), 9 ductal carcinomas in situ (DCIS), and 31 fibroadenomas from breast tissues and its relationship with the clinical features were determined using immunohistochemistry (peroxidase-conjugated polymer method, ChemMate™ Envision™ Detection kit). The positive immunostaining rates for OX40 in IDCa, DCIS and fibroadenomas from breast tissues were 85.0%, 66.7% and 38.7% respectively, showing a significant difference in OX40 expression among IDCa, DCIS and fibroadenoma of breast (z = 5.206, P = 0.001). Increased staining intensity of OX40 was associated with TNM stages (z = 2.112, P = 0.017). Meanwhile, a relation of OX40 expression with lymph node metastatic status in IDCa was found (P = 0.041). The expression of OX40L did not show any obvious difference among IDCa, DCIS and fibroadenomas from breast tissues. OX40L expression was also not related to histopathological parameters in IDCa except for progesterone receptor (PR) being positive (P = 0.005). However, a high coincidental positive rate for OX40 and OX40L was observed in biopsy samples with IDCa (P = 0.017, Kappa = 0.231). The present results suggest that high OX40 expression may be associated with malignant transformation, progression, invasion and metastasis in breast cancer biology.     

Genetic similarities and differences between lobular in situ neoplasia (LN) and invasive lobular carcinoma of the breast

One of the most controversial issues in breast pathology is whether lobular neoplasia (LN) is a risk factor or a precursor lesion of invasive lobular carcinoma (ILC). This is consequent to the fact that no conclusive data on the biology of LN exist. Molecular studies of LN and ILC are scanty, variable, and not consistent. Clonality of 12 cases of LN and ILC present simultaneously in the same block has been studied. Cells from both lesions were obtained by microdissection and were studied for mitochondrial DNA (mtDNA), D-loop sequencing, and neighbor-joining trees. Eight of the same cases were studied with comparative genomic hybridization (CGH) array to have additional data consistent with mtDNA. In all cases, loss of heterozygosity was studied for D16S496,locus 16q22.1 related to e-cadherin. It appears that no fewer than eight cases were genetically very similar (clonal) with mtDNA. Seven of these cases appeared also clonal with CGH array. It is concluded that in the present series, LN and ILC are genetically related lesions in the majority of cases and that LN might be the precursor of ILC.     

Central atypical papillomas of the breast: a clinicopathological study of 119 cases

The clinicopathological features of central intraductal papillomas of the breast presenting with florid usual ductal hyperplasia or atypical ductal hyperplasia (ADH) were analyzed in a retrospective series of 119 patients, whose lesions were sent to the Armed Forces Institute of Pathology from 1976 to 1990. After histological review considering predefined morphological and quantitative criteria, the 119 central papillomas were classified into 22 papillomas with florid usual ductal hyperplasia (18%), 40 papillomas with focal atypia (34%), 24 atypical papillomas (20%) and 33 carcinomas arising in a papilloma (28%). After a median period of follow-up of 110 months, 16 recurrences (5 papillomas, 2 carcinomas arising in a papilloma, 4 ductal carcinomas in situ, 5 invasive carcinomas) occurred. No statistically significant difference was observed in relation to recurrence for the various categories of papillomas. The presence of epithelial hyperplasia, ADH or lobular neoplasia in the surrounding breast as well as infarction of the papilloma were significant predictive factors of recurrence (P=0.02 and P=0.005, respectively, log-rank test). The main reason for the observed low rate of significant recurrences in this series was that epithelial atypia (whether comprising 20% or 60% of the papillary lesion) was, in most of the cases, localized in a confined lesion that was completely excised.     

Atypical breast lesions: a challenging pathological diagnosis and an uncertain malignant potential

Atypical epithelial breast lesions are a heterogeneous group of entities, the diagnosis of which can be challenging. In this review, we discuss the wide spectrum of atypical epithelial breast proliferations including atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), flat epithelial atypia (FEA), atypia in a papilloma, atypical microglandular adenosis, apocrine atypia and post neo-adjuvant chemotherapy associated atypia. We aim to review the histologic diagnostic criteria for these entities, with an emphasis on the salient morphologic features and differential diagnoses to consider, in order to provide a comprehensive and practical guide to their diagnosis.