The role of contrast-enhanced mammography in the preoperative evaluation of invasive lobular carcinoma of the breast.

AIM: To assess the performance of contrast-enhanced mammography (CEM) in the preoperative staging of invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS: The present study was a multicentre, multivendor, multinational retrospective study of women with a histological diagnosis of ILC who had undergone CEM from December 2013 to December 2021. Index lesion size and multifocality were recorded for two-dimensional (2D) mammography, CEM, and when available magnetic resonance imaging (MRI). Comparison with histological data was undertaken for women treated by primary surgical excision. Pearson correlation coefficients and Bland-Altman's analysis of agreement were used to assess differences with a significance level of 0.05. RESULTS: One hundred and fifteen ILC lesions were included, 46 (40%) presented symptomatically and 69 were screening detected. CEM demonstrated superior sensitivity when compared to standard mammography. The correlation between the histological size measured on the surgical excision specimen size was greater than with standard mammography (r=0.626 and 0.295 respectively, p=0.001), with 19% of lobular carcinomas not visible without a contrast agent. The sensitivity of CEM for multifocal disease was greater than standard mammography (70% and 20% respectively, p<0.0001). CEM overestimated tumour size by an average of 1.5 times, with the size difference increasing for larger tumour. When MRI was performed (n=22), tumour size was also overestimated by an average of 1.3 times. The degree of size overestimation was similar for both techniques, with the tumour size on CEM being on average 0.5 cm larger than MRI. CONCLUSION: CEM is a useful tool for the local staging of lobular carcinomas and could be an alternative to breast MRI.

NHS Breast Screening multidisciplinary working group guidelines for the diagnosis and management of breast lesions of uncertain malignant potential on core biopsy (B3 lesions).

Needle core biopsy is considered the histological diagnostic method of choice for screen-detected breast lesions. Although the majority are definitively diagnosed as normal, benign, or malignant, approximately 7% are categorised as B3, of uncertain malignant potential. These include a wide range of lesions with different risks of associated malignancy from <2% to approaching 40% from literature review in UK practice. Historically, these have typically been surgically excised as a diagnostic procedure but the majority are then proven to be benign. An alternative approach, for many of these lesions, is thorough sampling/excision by vacuum-assisted biopsy techniques to exclude the presence of co-existing carcinoma. This would potentially reduce the benign open biopsy rate whilst maintaining accuracy of cancer diagnosis. A group from the Radiology, Surgery, and Pathology NHS Breast Screening Programme Co-ordinating Committees and an additional co-opted expert were charged with review and development of guidelines for the clinical management of B3 lesions. The guidelines reflect suggested practice as stated by the NHS Breast Screening Programme and approved by the Royal College of Radiologists.

Factors influencing local control in patients undergoing breast conservation surgery for ductal carcinoma in situ.

BACKGROUND: The aim of our study was to assess various predictors for local recurrence (LR) in patients undergoing breast conservation surgery (BCS) for ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: An audit was performed of 582 consecutive patients with DCIS between Jan 1975 to June 2008. In patients undergoing BCS, local guidelines reported a margin of ≥10 mm during the above period. Guideline with regard to margin of excision changes soon after this period. We retrospectively analysed clinical and pathological risk factors for local recurrence in patients undergoing BCS. Statistical analysis was carried out using SPSS version 19, and a cox regression model for multivariate analysis of local recurrence was used. RESULTS: Overall 239 women had BCS for DCIS during the above period. The actuarial 5-year recurrence rate was 9.6%. The overall LR rate was 17% (40/239. LR was more common in patients ≤50 years: (10/31 patients, 32%) compared to patients > 50 years (30/208, 14%, P = 0.02). Forty three per cent of patients (6/14) with <5 mm margin developed LR which was significantly higher compared to patients with 5-9 mm margin (12%, 3/25) and with ≥10 mm margin (14%, 27/188, P = 0.01). On multivariate analysis age ≤50 years, <5 mm pathological margin were independent prognostic factors for local recurrence. CONCLUSION: Our study shows that younger age (≤50 years) and a margin < 5 mm are poor prognostic factors for LR in patients undergoing breast conservation surgery for DCIS.

The prognostic significance of B lymphocytes in invasive carcinoma of the breast.

Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20(+) cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20(+) B cells and higher tumour grade (r (s) = 0.20, P < 0.001), ER and PgR negativity (P < 0.001), and basal phenotype (P < 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20(+) cells, irrespective of location, was associated with significantly better BCSS (P = 0.037) and longer DFI (P = 0.001). In multivariate analysis, total CD20(+) B cell count (HR = 0.75, 95% CI = 0.58-0.96 for BCSS and HR = 0.72, 95% CI = 0.58-0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8(+) T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.

Tumour-infiltrating macrophages and clinical outcome in breast cancer.

BACKGROUND: Macrophages constitute a major component of the leucocytic infiltrate of tumours. Human studies show an association between tumour-associated macrophages and tumours with poor prognostic features. In breast cancer, the presence of macrophages has been correlated with increased angiogenesis and poor prognosis but little information is available about the independent prognostic role of macrophages infiltrating breast carcinomas. AIMS AND METHODS: This study used immunohistochemistry and tissue microarrays to assess the density and localisation of CD68 macrophages infiltrating 1322 breast tumours and to identify any relationship with clinicopathological factors and patient outcome. RESULTS: Tumour-infiltrating macrophages were present in the majority of tumours with a predominantly diffuse pattern. The density of distant stromal macrophages (infiltrating stroma away from the carcinoma, median count 14 cells) was higher than intratumoural (median zero cells) and adjacent stromal macrophages (median three cells). Higher total macrophage number was associated with higher tumour grade (r(s)=0.39, p<0.001), ER and PgR negativity, HER-2 positivity and basal phenotype (p<0.001). In univariate survival analysis, higher numbers of CD68 macrophages were significantly associated with worse breast cancer-specific survival (p<0.001) and shorter disease-free interval (p=0.004). However in multivariate model analysis, the CD68 macrophage count was not an independent prognostic marker. CONCLUSIONS: Macrophages are heterogeneous with different subsets having different functions. The present study suggests that overall macrophage numbers are not related to prognosis in breast cancer. However, further studies are needed to investigate the potential role of different subsets of macrophages.

The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast.

UNLABELLED: The new gene expression molecular taxonomy of breast cancer places medullary carcinoma in the basal group. The basal group is considered to have a poor prognosis, but medullary carcinoma is considered to have a better prognosis than other grade 3 carcinomas. The prognostic significance of tumour associated inflammation, an important feature of medullary carcinomas, remains controversial. The aim of this study was to assess the prognostic importance of medullary histological type and inflammation in breast cancer. One thousand five hundred and ninety-seven patients who received no systemic adjuvant treatment and who had a median follow up of 9.5 years were studied. RESULTS: Prominent inflammation was associated with high histological grade and with better survival [relative risk (RR) 0.57, 95% confidence intervals (CI) 0.44-0.74] on multivariate analysis. Typical and atypical medullary carcinomas (n=132) did not have significantly different survival and were grouped together. Medullary carcinoma did not have significantly different prognosis than grade 3 ductal carcinoma with prominent inflammation, but both had a better prognosis than grade 3 ductal carcinoma without prominent inflammation (P<0.0001 and P=0.03). These differences were independent of other prognostic factors. These results question the current separation of typical and atypical medullary carcinoma. Prominent inflammation is associated with a better prognosis, and may explain the better prognosis in medullary carcinoma compared with grade 3 ductal carcinoma without prominent inflammation. The good prognosis of medullary carcinoma emphasises the heterogeneity of basal-like breast carcinomas. Further studies are needed to investigate the difference in survival between medullary carcinoma and other forms of basal carcinomas and the role of inflammation in any such differences in behaviour.

Vascular invasion in breast cancer; an overview of recent prognostic developments and molecular pathophysiological mechanisms.

Vascular invasion (VI) is an essential step in breast cancer metastasis and the main cause of morbidity and mortality from the disease. Detection of VI in the primary tumour is a marker of metastatic potential. The prognostic value of VI in breast cancer has been known for more than four decades, but its application in clinical practice is still fraught with difficulties due to the limited number of studies conducted on large numbers of well-characterized patients with long-term follow-up. Detection of VI in the primary tumour is currently assessed using sections stained with haematoxylin and eosin, which has some disadvantages. A number of vascular markers have been used to improve detection of VI; however, their sensitivity and specificity, as endothelial markers, vary considerably. In this review we describe the evolution of the prognostic importance of VI and the recent pathomolecular mechanisms that contribute to the ability of breast cancers to invade through vessels, in addition to the types, locations and methods of detection of vascular invasion.

Predictive value of needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening.

AIMS: Breast needle core biopsy (NCB) is now a commonplace diagnostic procedure in breast cancer screening, providing accurate diagnoses of both benign and malignant lesions. However, NCB may result in the borderline diagnoses of lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4). The aim was to study a large series of B3 cases from population-based screening subjects in order to evaluate positive predictive values (PPVs) for malignancy. METHODS AND RESULTS: The results of 523 NCBs of women screened over a 7-year period (1999-2006) in the East Midlands region, UK, with a B3 diagnosis who underwent surgical excision, were reviewed and compared with the final excision histology. Five percent of NCBs were reported as B3. The most frequent histological subtypes were atypical intraductal epithelial proliferation (AIDEP) and radial scar/complex sclerosing lesion (RS/CSL). Final excision histology was benign in 417 (80%) and malignant in 106 (20%) subjects (60 ductal carcinoma in situ and 46 invasive carcinoma). Lesion-specific PPVs were as follows: AIDEP 32%; lobular neoplasia (LN) 30%; RS/CSL with AIDEP or LN 24%; RS/CSL without atypia 9%; papillary lesion with AIDEP or LN 36%; and papillary lesion without atypia 4%. Five of the 32 fibroepithelial lesions with cellular stroma were phyllodes tumours (four benign and one borderline). None of the five mucinous lesions on NCB was malignant. CONCLUSIONS: Our results show that approximately one-fifth of NCB of screen-detected breast lesions classified as B3 are malignant on excision, and the likelihood of malignancy varies substantially between different histological subtypes.

Vacuum-assisted excision of breast lesions of uncertain malignant potential (B3) - an alternative to surgery in selected cases.

To assess whether vacuum-assisted excision (VAE) is a safe alternative to surgery in the treatment of breast lesions of uncertain malignant potential (B3) in which no atypia is present on needle core biopsy (NCB). Forty two VAE procedures were performed for B3 lesions. Twenty four (57%) were papillary lesions. Eighteen (43%) were radial scars. Two patients (4.7%) were upgraded to carcinoma at VAE. Two patients with papillary lesions went on to develop cancer in the same breast (at 24 and 41 months post VAE). No cancer developed in the radial scar group. Eight patients (19%) had surgery - four for carcinoma, two for radial scars missed at VAE excision and two for symptomatic papillomatosis. Follow-up mammography after VAE of radial scars often showed residual distortion. VAE can be a safe alternative to surgery in the treatment of B3 lesions without atypia, providing thorough multidisciplinary discussion has taken place.

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.

Recent developments in the histological diagnosis of spindle cell carcinoma, fibromatosis and phyllodes tumour of the breast.

This article reviews recent advances in the diagnosis of these three unusual tumours of the breast. Spindle cell carcinoma needs to be considered in the differential diagnosis of many mammary spindle cell lesions: it is important to be aware of the wide range of appearances, including the recently described fibromatosis-like variant. Immunohistochemistry using a broad panel of cytokeratin antibodies is needed to exclude spindle cell carcinoma; there is frequent expression of basal cytokeratins and p63. CD34 is often expressed by the stroma of phyllodes tumours, but does not appear to be expressed by spindle cell carcinoma or fibromatosis. Nuclear beta-catenin is found in about 80% of fibromatoses, but can also be seen in spindle cell carcinomas and phyllodes tumours. Two recent studies have described features useful in the distinction of phyllodes tumour and fibroadenoma on core biopsy, including increased cellularity, mitoses and overgrowth of the stroma, adipose tissue in the stroma and fragmentation of the biopsy specimen. Periductal stromal tumour is a recently described biphasic tumour composed of spindle cells around open tubules or ducts (but no leaf-like architecture) with frequent CD34 expression. The overlap of morphology with phyllodes tumour suggests that it may be best regarded as a variant of phyllodes tumour.

The expression of Wilms' tumour-1 and Ca125 in invasive micropapillary carcinoma of the breast.

AIM: Metastases from ovarian serous papillary carcinoma to the breast and primary invasive micropapillary carcinoma of the breast are histologically similar. The distinction is clinically important to ensure appropriate management. Wilms' tumour-1 (WT1) and Ca125 are frequently expressed in serous papillary carcinomas, and uncommonly in unselected mammary carcinomas. One previous study found Ca125 expression in 69% of invasive micropapillary carcinomas. The aim was to assess the frequency of expression of WT1 and Ca125 in invasive micropapillary carcinoma. METHODS AND RESULTS: Twenty-five of 34 invasive micropapillary carcinomas showed no nuclear expression of WT1. The remaining nine tumours showed weak to moderate immunoreactivity in 1-10% of nuclei. Six of these nine tumours also contained ductal carcinoma in situ, which expressed WT1 in five of the six. Membranous or cytoplasmic expression of Ca125 was found in seven tumours. CONCLUSION: Nuclear WT1 expression is present in a minority of invasive micropapillary carcinomas and, when present, expression is focal. The frequency of expression of Ca125 was similar to the results in unselected mammary carcinoma. Thus, these markers are useful members of the immunohistochemical panel for the distinction of mammary invasive micropapillary carcinoma from ovarian serous papillary carcinoma.

Histological features useful in the distinction of phyllodes tumour and fibroadenoma on needle core biopsy of the breast.

AIM: To identify features useful in distinguishing phyllodes tumours from fibroadenomas on core biopsy. METHODS AND RESULTS: Starting from the diagnosis made on the surgical specimen, 12 features in the previous core biopsy specimens were analysed. Thirty-six phyllodes tumours had 44 previous core biopsy specimens, which were reported as fibroadenoma in 11 and spindle cell lesion of uncertain nature in one, and included phyllodes tumour in the differential diagnosis in 32. The lesions with a core diagnosis of fibroadenoma were excised largely because they were growing or exceeded 30 mm; review of the corresponding surgical specimen showed heterogeneous stromal cellularity. Thirty-eight fibroadenomas had previous core biopsy specimens reported as fibroadenoma in 37, and one of which included phyllodes tumour in the differential diagnosis. The following four features were significantly more common in cores from phyllodes tumours and had a kappa statistic of > 0.6 in a reproducibility study: stromal cellularity increased in at least 50% compared with typical fibroadenoma, stromal overgrowth (x10 field with no epithelium), fragmentation and adipose tissue within stroma. CONCLUSIONS: This study describes features useful in the diagnosis of phyllodes tumour on core biopsy. Some core biopsy specimens from phyllodes tumours show features of fibroadenoma on core biopsy because of tumour heterogeneity.

Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression.

AIM: To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours. METHODS AND RESULTS: The expression pattern of basal cytokeratins (CK5/6 and CK14), oestrogen, progesterone and androgen receptors, epidermal growth factor receptor, HER2, BRCA1, P-cadherin and myoepithelial markers (smooth muscle actin and p63) were studied in a well-characterized series of invasive breast carcinoma (1872 cases) with long-term follow-up using immunohistochemistry and tissue microarray. Although the additional markers were associated with basal CK expression, they did not serve to improve recognition of cases with differing outcome when compared with basal CKs alone and, if used to define cases, reduced considerably the proportion of cases allocated to this poor prognostic type of breast cancer. CONCLUSION: BP can be defined based on the expression of basal CKs regardless of the expression of other markers.

NHSBSP type 1 interval cancers: a scientifically valid grouping?

AIM: To assess whether there are differences in the pathological features or survival between the new National Health Service Breast Screening Programme (NHSBSP) interval cancer classification system category of type 1 interval cancers, and the previously used, separate categories of occult, unclassified, and true interval cancers. MATERIALS AND METHODS: The prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor status, and histological type) and survival of 428 type 1 interval invasive breast cancers were analysed by subgroup (occult, unclassified and true interval). RESULTS: Occult cancers compared with other type 1 interval cancers were of significantly lower grade [38 of 52 (73%) versus 151 of 340 (44%) grade 1 or 2, p=0.0005], more likely to be smaller size [37 of 51 (73%) versus 158 of 341 (46%) <20mm, p=0.0003] and more frequently of lobular type at histology [14 of 42 (32%) versus 50 of 286 (17%), p=0.03]. There was no significant difference in pathological features of unclassified tumours compared with other type 1 tumours. There was no significant survival difference between different type 1 subgroups (p=0.12). CONCLUSION: The NHSBSP type 1 interval cancers are a heterogeneous grouping with markedly differing pathological features. However, no significant survival difference is seen between the different type 1 subgroups.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990-1999.

UNLABELLED: The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. AIMS: Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. METHODS: The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980-1986 (n=892) and 1990-1999 (n=2,238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. RESULTS: Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. CONCLUSION: The updated survival figures overall and for each Prognostic group for the NPI are presented.

Interval breast cancers: prognostic features and survival by subtype and time since screening.

OBJECTIVES: To investigate the hypothesis that interval cancers arising soon after the previous screen and true interval cancers are biologically aggressive and have a relatively poor prognosis compared with other interval cancers, and to assess which prognostic features are relevant to interval cancers. METHODS: Analysis of prognostic pathological features (grade, lymph node stage, size, vascular invasion, oestrogen receptor [ER] status and histological type), radiological features (comedo/non-comedo calcification and spiculation) and survival for 538 invasive interval breast cancer cases by type and time since previous screen. RESULTS: Late interval cancers were less likely to be lymph node positive (13 versus 43%, P = 0.003). Type 1 interval cancers were more likely to be histological grade 3 than type 2 (minimal signs) and type 3 (false-negative) intervals (52 versus 35%, P = 0.05). Type 3 interval cancers were more likely to have lobular features than other intervals (47 versus 20%, P < 0.0001). There was no significant survival difference by interval cancer type (P = 0.64) or interval year (P = 0.83). At univariate analysis of all interval cancers, tumour size, grade, nodal stage, ER status, vascular invasion and comedo calcification were associated with survival. On multivariate analysis of prognostic features significant at univariate analysis, nodal stage (P value = 0.009), tumour size (P = 0.001), ER status (P < 0.0001) and vascular invasion (P < 0.0001) maintained independent significance. CONCLUSIONS: Our study shows that true intervals and interval cancers arising quickly after screening do not have a worse prognosis than other interval cancers, and that interval cancers have a unique set of prognostic features.

Unusual benign breast lesions.

The purpose of this article is to show examples of the radiological (mammography and/or ultrasound) and pathological appearances of unusual benign breast lesions. The conditions covered are granular cell tumours, fibromatosis, nodular fasciitis, myofibroblastomas, haemangiomas, neurofibromas, and leiomyomas. The article includes the first published description of the ultrasound appearance of a myofibroblastoma. Knowledge of these appearances may help confirm or refute radiological-pathological concordance of percutaneous biopsy results during multidisciplinary assessment of these lesions and aid patient management.