Deciphering the Clinical Behaviour of Invasive Lobular Carcinoma of the Breast Defines an Aggressive Subtype.

BACKGROUND: Invasive lobular carcinoma (ILC), the most common special type of breast cancer (BC), has unique clinical behaviour and is different from invasive ductal carcinoma of no special type (IDC-NST). However, ILC further comprises a diverse group of tumours with distinct features. This study aims to examine the clinicopathological and prognostic features of different variants of ILC, with a particular focus on characterising aggressive subtypes. METHODS: A large (n = 7140) well-characterised and histologically reviewed BC cohort with treatment and long-term follow-up data was investigated. The cohort was classified based on the WHO classification of tumours into main histological subtypes, including ILC and IDC-NST. ILCs were further classified into variants. Clinicopathological parameters and patient outcomes in terms of BC-specific survival (BCSS) and disease-free survival (DFS) were evaluated. RESULTS: ILC constituted 11% of the cohort. The most common non-classic ILC variants were pleomorphic (pILC) and solid (sILC), constituting 19% of ILC. Compared to classic and related variants (alveolar, trabecular, papillary, and tubulolobular; cILC), pILC and sILC variants were associated with aggressive tumour characteristics. The histologic grade of ILC was an important prognostic variable. The survival patterns identified an aggressive ILC subtype encompassing pILC and high-grade sILC. These tumours, which comprised 14% of the cases, were associated with clinicopathological characteristics of poor prognosis and had high BC-specific death and recurrence rates compared not only to cILC (p < 0.001) but also to IDC-NST (p = 0.02) patients. Contrasting this, cILC patients had significantly longer BCSS and DFS than IDC-NST patients in the first 10 to 15 years of follow-up. Adjuvant chemotherapy did not improve the outcome of patients with aggressive ILC subtypes. CONCLUSIONS: pILC and high-grade sILC variants comprise an aggressive ILC subtype associated with poor prognostic characteristics and a poor response to chemotherapy. These results warrant confirmation in randomised clinical trials.

Perception of cauliflower ear amongst combat sport athletes.

OBJECTIVE: Cauliflower ear, or "hematoma auris," is a permanent condition that is typically viewed as a deformity. Despite this, it has anecdotally been observed that combat sport athletes view cauliflower ear as a respected aesthetic trait. This study characterizes and quantifies the differences in initial impressions of subjects with cauliflower ear between combat sport athletes and the general population. METHODS: In a cross-sectional survey, participants were shown frontal and profile views of four subjects with cauliflower ear and five control subjects. Respondents rated the subjects on a scale of 0-100 in perceived success, attraction, approachability, and affect display. Numeric scores were compared between combat sport athletes and the general population. Additionally, first impressions were categorized into positive, neutral, or negative classes via latent class analysis (LCA). RESULTS: 678 combat sport athletes and 129 general casual observers participated in the survey. Combat sport athletes rated subjects with cauliflower ear significantly more favorably than respondents in the general population in all personal attributes: perceived success (+4.03, 95 % CI:1.8-6.2, p = 0.0003), attractiveness (+4.11, 95 % CI:1.8-6.4, p = 0.0005), approachability (+11.57, 95 % CI: 8.4-14.7, p < 0.0001), and affect display (+4.14, 95 % CI: 1.9-6.3, p = 0.0002). They also had approximately seven times greater odds (95 % CI:4.0-12.6, p < 0.001) of reporting a positive first impression of a person with cauliflower ear than the general population. CONCLUSION: Confirming anecdotal observation, the combat sports group had a more positive perception of cauliflower ear than the general population. Conditions that are typically viewed as deformities can be looked upon favorably in specific subpopulations.

Should a borderline negative HER2 result in a core biopsy of invasive carcinoma of the breast have HER2 assessment repeated in the excision specimen?

AIM: The 2015 UK guidelines for HER2 assessment in breast cancer recommended repeat assessment if the core biopsy was scored as 2+ on HER2 immunohistochemistry (IHC) with borderline negative in situ hybridisation (ratio of number of HER2 to chromosome 17 centromere copies of 1.8-1.99). This case series aimed to assess the value of such repeat assessment in the surgical specimen, in particular the proportion that were HER2 positive. METHODS: Details of biopsies with 2+ IHC and borderline negative in situ hybridisation were extracted from a database. The results of repeat HER2 testing in the surgical specimen for this cohort study were then obtained. RESULTS: 112 patients with no preoperative treatment had repeat assessment: 4 were 3+ and 16 were 2+ amplified. Of 14 with preoperative chemotherapy, 1 was 3+ and 4 were 2+ amplified. All the 2+ amplified carcinomas had a HER2 to chromosome 17 ratio less than 4, in 50% the ratio was between 2.0 and 2.2, and in 50% the HER2 copy number was less than 4. CONCLUSIONS: Repeat assessment yielded 4% 3+ results and 14% 2+ amplified carcinomas but with low level amplification. These results suggest that retesting of borderline negative HER2 cases should be optional and no longer mandatory.

The Clinical and Biological Significance of Estrogen Receptor-Low Positive Breast Cancer.

Estrogen receptor (ER) status in breast cancer (BC) is determined using immunohistochemistry (IHC) with nuclear expression in ≥1% of cells defined as ER-positive. BC with 1%-9% expression (ER-low-positive), is a clinically and biologically unique subgroup. In this study, we hypothesized that ER-low-positive BC represents a heterogeneous group with a mixture of ER-positive and ER-negative tumor, which may explain their divergent clinical behavior. A large BC cohort (n = 8171) was investigated and categorized into 3 groups: ER-low-positive (1%-9%), ER-positive (≥10%), and ER-negative (<1%) where clinicopathological and outcome characteristics were compared. A subset of ER-low-positive cases was further evaluated using IHC, RNAscope, and RT-qPCR. PAM50 subtyping and ESR1 mRNA expression levels were assessed in ER-low-positive cases within The Cancer Genome Atlas data set. The reliability of image analysis software in assessment of ER expression in the ER-low-positive category was also assessed. ER-low-positive tumors constituted <2% of BC cases examined and showed significant clinicopathological similarity to ER-negative tumors. Most of these tumors were nonluminal types showing low ESR1 mRNA expression. Further validation of ER status revealed that 45% of these tumors were ER-negative with repeated IHC staining and confirmed by RNAscope and RT-qPCR. ER-low-positive tumors diagnosed on needle core biopsy were enriched with false-positive ER staining. BCs with 10% ER behaved similar to ER-positive, rather than ER-negative or low-positive BCs. Moderate concordance was found in assessment of ER-low-positive tumors, and this was not improved by image analysis. Routinely diagnosed ER-low-positive BC includes a proportion of ER-negative cases. We recommend repeat testing of BC showing 1%-9% ER expression and using a cutoff ≥10% expression to define ER positivity to help better inform treatment decisions.

Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland -on behalf of the UK national coordinating committee for breast pathology.

BACKGROUND: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. PATIENT AND METHODS: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period. RESULTS: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group. CONCLUSION: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy.

Second opinion (external specialist referral) practice of breast pathology: the Nottingham experience.

AIMS: Breast pathology is a challenging field, and discrepancies in diagnoses exist and can affect patient management. This study aims to review a breast referral practice and assess the pattern and frequency of breast lesions sent for an external expert review and evaluate potential impacts on patients' care. METHODS AND RESULTS: Seven hundred and forty cases that were referred to Nottingham City Hospital for a second opinion between 2019 and 2022 which have slides and reports were retrieved and reviewed. Reasons for referral, initial diagnosis, proffered specialist opinion and any discrepancy or potential impacts of management were assessed. The most frequent entities were papillary lesions (19%), fibroepithelial lesions (17%), invasive carcinomas that were sent for confirmation of the invasive diagnosis or subtyping of the invasive tumour (17%), intraductal epithelial proliferation with atypia (9%) and spindle cell lesions (8%). Other entities included biphasic tumours such as adenomyoepithelioma, as well as vascular and nipple lesions. Few cases were sent for prognostic classification or comments on the management, and in occasional cases no initial diagnosis was offered. After reviewing the cases by the expert pathologists, the initial diagnosis was confirmed or one of the suggested diagnoses was preferred in 79% of cases, including 129 cases (17%) in which the opinion resulted minor changes in the management. Significant changes in the classification of lesions were made in 132 cases (18%) which resulted in significant change in the patient management recommendation. In 14 cases (2%) a final classification was not possible, and further specialist opinion was obtained. Comments on the differential diagnosis and advice on further patient management were provided in most cases. CONCLUSIONS: This study demonstrates the value of external referral of challenging, rare and difficult to classify breast lesions. It also highlights the most common breast lesions that are likely to be challenging, and specialist opinion can refine their classification to improve patient care.

Preoperative diagnosis of ductal carcinoma in situ of the breast over a 24-year period.

AIMS: The method of diagnosis of ductal carcinoma in situ (DCIS) has changed since the 1980s. The aim of this audit was to assess changes in the preoperative diagnosis of DCIS since the introduction of needle core biopsy, particularly the proportion with a preoperative biopsy diagnosis of DCIS. METHODS AND RESULTS: The preoperative diagnoses of patients with a final diagnosis of DCIS in the surgical specimen were reviewed (i) in 809 patients who presented through breast screening from 1997 to 2021, and (ii) in all patients in 5 individual years at 5-year intervals from 2000 to 2020 (254 in total). For screening-detected DCIS the proportion with a preoperative diagnosis of DCIS increased from 75% to 98% over the study period. In a detailed analysis of all cases of DCIS in 5 separate years the proportion with a preoperative diagnosis of DCIS increased from 68% in 2000 to 96% in 2020. For high-grade DCIS the proportion increased from 87% to 97%, and for low- or intermediate-grade DCIS from 48% to 93%. The proportion of women who had vacuum-assisted biopsy increased from 7% in 2000 to 58% in 2015. There was a small increase in the number of biopsies that had basal cytokeratin and oestrogen receptor immunohistochemistry to aid diagnosis. CONCLUSION: There has been an increase in the preoperative diagnosis of DCIS, particularly of low- or intermediate-grade, over the last two decades. The increasing use of vacuum-assisted biopsy is likely to be a major contributory factor to this increase.

UK recommendations for HER2 assessment in breast cancer: an update.

The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 and HER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.

Probabilistic Prediction of Laboratory Test Information Yield.

Low-yield repetitive laboratory diagnostics burden patients and inflate cost of care. In this study, we assess whether stability in repeated laboratory diagnostic measurements is predictable with uncertainty estimates using electronic health record data available before the diagnostic is ordered. We use probabilistic regression to predict a distribution of plausible values, allowing use-time customization for various definitions of "stability" given dynamic ranges and clinical scenarios. After converting distributions into "stability" scores, the models achieve a sensitivity of 29% for white blood cells, 60% for hemoglobin, 100% for platelets, 54% for potassium, 99% for albumin and 35% for creatinine for predicting stability at 90% precision, suggesting those fractions of repetitive tests could be reduced with low risk of missing important changes. The findings demonstrate the feasibility of using electronic health record data to identify low-yield repetitive tests and offer personalized guidance for better usage of testing while ensuring high quality care.

The frequency and clinical significance of centromere enumeration probe 17 alterations in human epidermal growth factor receptor 2 immunohistochemistry-equivocal invasive breast cancer.

BACKGROUND AND AIMS: Chromosome 17 alterations affect the assessment of HER2 gene amplification in breast cancer (BC), but its clinical significance remains unclear. This study aimed to identify the prevalence of centromere enumeration probe 17 (CEP17) alterations, and its correlation with response to neoadjuvant therapy (NAT) in BC patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry-equivocal score. METHODS AND RESULTS: A large BC cohort (n = 6049) with HER2 immunohistochemistry score 2+ and florescent in-situ hybridisation (FISH) results was included to assess the prevalence of CEP17 alterations. Another cohort (n = 885) with available clinicopathological data was used to evaluate the effect of CEP17 in the setting of NAT. HER2-amplified tumours with monosomy 17 (CEP17 copy number < 1.5 per nucleus), normal 17 (CEP17 1.5-< 3.0) and polysomy 17 (CEP17 ≥ 3.0) were observed in 16, 59 and 25%, respectively, compared with 3, 74 and 23%, respectively, in HER2-non-amplified tumours. There was no significant relationship between CEP17 alterations and pathological complete response (pCR) rate in both HER2-amplified and HER2-non-amplified tumours. The independent predictors of pCR were oestrogen (ER) negativity in HER2-amplified tumours [ER negative versus positive; odds ratio (OR) = 11.80; 95% confidence interval (CI) = 1.37-102.00; P = 0.02], and histological grade 3 in HER2 non-amplified tumours (3 versus 1, 2; OR = 5.54; 95% CI = 1.61-19.00; P = 0.007). CONCLUSION: The impacts of CEP17 alterations are not as strong as those of HER2/CEP17 ratio and HER2 copy number. The hormonal receptors status and tumour histological grade are more useful to identify BC patients with a HER2 immunohistochemistry-equivocal score who would benefit from NAT.

Facial Artery Musculomucosal Flap Operative Techniques.

SUMMARY: Regional flaps are an important component of the reconstructive ladder and represent a versatile option in reconstructing various oral cavity defects. An axial buccal flap based on the facial artery, the facial artery musculomucosal flap, was first described by Pribaz et al. and has been shown to have good functional outcomes with minimal morbidity. Indeed, other surgeons have praised its favorable arc of rotation, reliability, and role as an alternative to free tissue transfer, with shorter duration of general anesthesia and allowance for earlier postoperative mobilization. The facial artery musculomucosal flap has significant versatility, as it can be superiorly or inferiorly based and can be performed in either single- or two-stage fashion. It is of particular advantage for reconstruction of the oral cavity (retromolar trigone, hard palate, alveolar ridge, lip, tongue, and floor of mouth), oropharynx (tongue base, lateral pharynx, and soft palate), and sinonasal structures. Despite its advantages, its widespread use has been limited by a lack of familiarity and difficulty in safely raising a reliable flap consistently. The senior author (S.C.D.) has successfully utilized a high volume of facial artery musculomucosal flaps with a low complication rate in a broad array of oral cavity and oropharyngeal defects. In this article, the authors share technical details on how to harvest and inset this flap by incorporating key landmarks in a reliable fashion.

Angiosarcoma arising in the capsule of a mammary silicone implant.

A 40-year-old woman with silicone implants inserted 21 years before presented with sudden onset of painful right breast swelling. Clinical examination revealed a firm swollen breast with appearance of old bruising. Ultrasound showed fluid around the implant. Cytology of the fluid showed cells with large pleomorphic nuclei with prominent nucleoli including elongated forms and very occasional vacuoles. The cell block also contained small fragments with atypical spindle cells around slit-like spaces that were positive for CD31 and CD34. MRI showed a 25 mm serpiginous area of enhancement on the inner aspect of the fibrous capsule with haematoma between the capsule and the implant. The capsule and adjacent area were excised. Histology showed angiosarcoma extending from the inner aspect of the capsule into the cavity around the implant. The location of the tumour on the inner aspect of the capsule is the same site that breast implant associated anaplastic large cell lymphomas arise and suggests a possible causal link between the implant and the angiosarcoma. This case emphasises the value of cytological assessment of fluid around breast implants and the role of cell blocks and immunohistochemistry.

Fibroepithelial tumours of the breast-a review.

Fibroepithelial tumours of the breast are biphasic neoplasms composed of both epithelial and stromal elements, including the common fibroadenoma and the infrequent phyllodes tumour. The admixture of epithelium and stroma in the fibroadenoma shows intra- and pericanalicular patterns, and may display a variety of histological changes. Fibroadenoma variants include the cellular, juvenile, myxoid and complex forms. The cellular fibroadenoma may be difficult to distinguish from the benign phyllodes tumour. Stromal mitotic activity can be increased in fibroadenomas in the young and pregnant patients. Phyllodes tumours, neoplasms with the potential for recurrence, show an exaggerated intracanalicular growth pattern with broad stromal fronded architecture and stromal hypercellularity. They are graded into benign, borderline and malignant forms based on histological assessment of stromal features of hypercellularity, atypia, mitotic activity, overgrowth and the nature of the tumour borders. Classification of phyllodes tumours is imperfect, compounded by tumour heterogeneity with overlapping microscopic features among the different grades, especially in the borderline category. Malignant phyllodes tumours can metastasise and cause death. Determining which phyllodes tumours may behave aggressively has been difficult. The discovery of MED12 mutations in the pathogenesis of fibroepithelial tumours, together with other gene abnormalities in the progression pathway, has allowed refinements in diagnosis and prognosis.

Effectiveness of percutaneous vacuum-assisted excision (VAE) of breast lesions of uncertain malignant potential (B3 lesions) as an alternative to open surgical biopsy.

OBJECTIVES: Traditionally B3 breast lesions are treated surgically, but overtreatment is a concern, as the majority have a final benign diagnosis. A national screening program introduced vacuum-assisted excision (VAE) for managing B3 lesions in late 2016. This retrospective study aimed to assess the outcomes associated with this approach. METHODS: All B3 lesions diagnosed between 01/2017 and 12/2019 were identified at two centres. Information was obtained on the initial biopsy and final histology, and method of VAE image guidance, needle size and number of cores. Lesions were excluded if there was cancer elsewhere in the breast at the time of diagnosis; the lesion was not suitable for VAE due to position in the breast or had B3 pathology for which open biopsy was still required. The final decision to offer VAE was always made at a multidisciplinary meeting (MDM). Risk difference was used to test the significance at p ≤ .05. RESULTS: In total, 258 B3 lesions were diagnosed, 105 (40.7%) met the inclusion criteria and underwent VAE. VAE was performed under X-ray (89/105) or ultrasound guidance (16/105), taking an average of 18.5 cores with the 10-G needle or 10.8 cores with the 7-G needle. Nine cases (8.6%) were upgraded to a malignant diagnosis following VAE. Malignancy was found in 15.5% (9/58) of B3 lesions with epithelial atypia, but in none without atypia (0/47) (p = .004). No new lesions or malignancy has occurred at the site of the VAE with an average mammographic follow-up of 2.2 years. CONCLUSION: Upgrade to malignancy following VAE was uncommon (8.6%) and associated with atypia in the initial biopsy. VAE is an alternative approach to the management of B3 lesions, reducing open surgical procedures. KEY POINTS: • Upgrade to malignancy after a vacuum-assisted excision of a B3 breast lesion is uncommon with an 8.6% upgrade rate. • The risk of a malignant diagnosis after a vacuum-assisted excision was significantly higher for B3 lesions with atypia compared to those without (+15.5% difference, p = .004).

Retrospective observational study of HER2 immunohistochemistry in borderline breast cancer patients undergoing neoadjuvant therapy, with an emphasis on Group 2 (HER2/CEP17 ratio ≥2.0, HER2 copy number <4.0 signals/cell) cases.

BACKGROUND: The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). METHODS: 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. RESULTS: 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). CONCLUSION: No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.

Malignant phyllodes tumour of the breast mimicking endometriosis.

A 63-year-old woman presented with a clinically malignant mass. Core biopsy showed features resembling endometriosis. The glands were GATA3 and oestrogen receptor positive consistent with mammary origin and had no myoepithelial layer. The excision also showed a fibroepithelial component with stromal overgrowth, frequent mitoses and invasive margin consistent with a malignant phyllodes tumour. KMT2D and SETD2 mutations were present in both the conventional phyllodes tumour and endometriosis-like areas and are also described in endometriosis raising interesting questions about these lesions. This unusual pattern is a potential diagnostic pitfall, so it is helpful to be aware of it.