Aims
Confirmation of a breast origin for triple‐negative breast cancer (TNBC) is sometimes problematic. The traditional breast markers GATA‐binding protein 3 (GATA3), mammaglobin (MGB) and gross ...cystic disease fluid protein 15 (GCDFP15) have shown limitations in identifying TNBC. Here, we aimed to examine the diagnostic potential of the newly proposed TNBC marker, Sry‐related high‐mobility‐group/HMG box 10 (SOX10).
Methods and results
We analysed and compared SOX10 expression with GATA3, MGB and GCDFP15 expression in a test cohort of 1838 invasive breast cancers (IBCs) by using tissue microarrays. The findings from the test cohort were further examined with a validation cohort of 42 TNBCs in whole sections. The overall expression rates of SOX10, GATA3, MGB and GCDFP15 were 6.9%, 83.1%, 47.0%, and 34.8%, respectively. Among the TNBCs within this cohort, the expression rates of SOX10, GATA3, MGB and GCDFP15 were 31.3%, 34.5%, 27.9%, and 25.2%, respectively. SOX10 was strongly associated with TNBC (P < 0.001), whereas all other traditional markers were associated with non‐TNBC (P < 0.001 for all). In addition, SOX10 was more correlated to basal‐like breast cancer (BLBC) (P = 0.001) than five‐marker‐negative subtype among the TNBCs. A high expression rate of SOX10 (81%) was confirmed in the validation cohort. Additionally, SOX10 expression was inversely correlated with GATA3 and GCDFP15 expression, so they may complement each other in TNBC detection. The SOX10–GATA3 combination yielded a sensitivity of 60.3% for TNBC detection in the test cohort.
Conclusion
SOX10 is a reliable marker for identifying TNBC, and complements GATA3. The SOX10–GATA3 combination may be used as a sensitive TNBC marker.
The latest ASCO/CAP guideline has recommended to report oestrogen receptor (ER) low cases (ER
; 1-10%) as "ER low positive category", prompting us to compare the clinicopathologic features, ...biomarkers, survival and treatment of the ER
cases with other subgroups (ER negative (ER
) and ER high (ER
)). ER
cases revealed more similar clinicopathologic and biomarker profiles (including younger age, larger tumour, high proliferation, HER2 and basal markers expression) to ER
than ER
cancers. The ER
cases receiving hormonal therapy showed a similarly poor outcome as ER
cancers. However, majority of ER
cases were downstaged to stage I in the 8th AJCC pathological prognostic staging, highlighting a risk of potential under treatment. Overall, our data highlighted the differences of ER
from other ER
cases and their management should be considered separately.
Aims
Atypical ductal hyperplasia (ADH) of breast is increasingly diagnosed in core needle biopsy (CNB). As higher‐grade lesions were found in the excision in a substantial proportion of ADH on CNB, ...factors predicting risk of subsequent upgrade are clinically significant. This study aims to investigate relevant histopathological factors in CNB that could predict diagnostic upgrade at excision.
Methods and results
One hundred and forty‐three cases of CNB with paired subsequent excision were evaluated for multiple clinicopathological parameters related to CNB sampling, ADH morphology, calcification and other co‐existing histological features, and which of these parameters were associated with diagnostic upgrade at subsequent excisions were determined. Forty‐eight cases (34.3%) were upgraded to malignancy, including 15 invasive cancers and 33 ductal carcinomas in situ (DCIS). An increased tissue area occupied by ADH (P = 0.026), a higher number of ADH foci (P = 0.004), the presence of solid pattern (P = 0.037) and older age (P = 0.012) were positively associated with upgrade, while negative associations were found with the presence of micropapillary pattern (P = 0.025), co‐existing columnar cell lesions (CCL) (P = 0.001) and the presence of calcifications (P = 0.009). Multivariate logistic regression analysis showed that the number of ADH foci (HR = 2.810, P = 0.013) was an independent positive predictor, while co‐existing CCL (HR = 0.391, P = 0.013) was an independent negative predictor for upgrade.
Conclusions
Patients with ADH in CNB showing the presence of co‐existing CCL and a lower number of ADH foci have a lower risk of disease upgrade at excision, and are potential candidates for observation‐only management.
Purpose
Despite numerous studies on the utility of GATA-3 as breast cancer marker, its comparison with other breast markers, its concordance between primary and metastatic tumors and its expression ...in primary cancers from sites with frequent breast metastases remains unclear.
Methods
To address these questions, totally 993 invasive breast cancers (IBC), 254 paired nodal metastases, 23 distant metastases, and 208 lung carcinomas were included. GATA-3 expression was analyzed by immunohistochemistry and compared to other breast markers gross cystic disease fluid protein 15 (GCDFP-15) and mammaglobin (MGB).
Results
GATA-3 was expressed in 82.5% of IBC, predominantly in luminal (93.9%), and lower in non-luminal cancers 59.6% of HER2 overexpressing (HER2-OE) and 38.1% of triple negative breast cancer (TNBC) subtypes. GATA-3 identified more IBC than GCDFP-15 (23.9%) and MGB (46.6%). However, MGB showed a comparable sensitivity for non-luminal cancers to GATA-3. Combining MGB and GATA-3 improved sensitivity for both HER2-OE (80.8%) and TNBC cases (55.4%). GATA-3 showed a high sensitivity for nodal metastases and distant metastases, with good concordance with primary tumors. GATA-3 was expressed in 1.0% of lung carcinomas, with sensitivity and specificity of 82.5 and 99.0% in differentiating IBC and lung carcinoma.
Conclusions
GATA-3 expression was the highest in luminal breast carcinomas, and showed higher sensitivity than GCDFP-15 and MGB. However, in the poorly differentiated IBC, its utility was still limited. One should be aware of the possible GATA-3 expression in lung carcinomas.
The latest World Health Organization (WHO) classification categorized invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiations into neuroendocrine neoplasms (including ...well‐differentiated neuroendocrine tumor NET and poorly differentiated neuroendocrine carcinoma NEC) and IBC no special type with NE features (IBC‐NST‐NE). However, little is documented of the clinical significance of this classification; also the precise thresholds and choices of NE markers were variable. In the current study, a large cohort of patients with IBC with NE differentiation were morphologically classified based on the WHO criteria and the clinical relevance of expression of different NE markers (synaptophysin SYN, chromogranin CG, and CD56) was evaluated. Among 1,372 IBCs, 52 NET (3.8%) and 172 IBC‐NST‐NE (12.5%) were identified. Compared with the IBC–no NE cases, NET and IBC‐NST‐NE were similarly associated with positive estrogen receptor (ER) expression and lower grade (p < .001). For patient outcome, IBC‐NST‐NE, but not NET, demonstrated significantly worse survival than the IBC–no NE cases. Based on high (≥50%) and low (<50%) expression for each NE marker, independent poor disease‐free survival for SYNloCGlo and SYNhiCGlo cancers (IBC–no NE cases as references, hazard ratio HR, ≤1.429; p ≤ .026) was found. Interestingly, SYN and CG expression correlated with each other and they shared similar clinicopathologic characteristics; but not with with CD56. In addition, CD56‐only positive cases were associated with hormone receptors negativity and basal markers positivity (p ≤ .019), and patients’ outcome was similar to IBC–no NE cancers. Our findings suggested that NE markers expression may provide information to fine tune treatment strategy. The relevance of CD56 as NE marker requires further studies.
Implications for Practice
Invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiation are heterogeneous in clinicopathologic parameters, biomarker expression, and prognosis. However, there are no specific therapies targeting NE differentiation, and all carcinomas with any NE differentiation are treated similarly as other IBCs. The results of this study suggest that stratification based on NE marker expression levels may provide added prognostically pertinent information, aiding better treatment strategy. In addition, CD56‐only positive carcinomas showed a different clinicopathologic and biomarker expression profile compared with those with chromogranin and synaptophysin expression. Relevance of CD56 as an NE marker requires further studies.
The prognostic relevance of neuroendocrine differentiation in primary infiltrating breast carcinomas is uncertain. This article evaluates the incidence of carcinoma showing immunohistochemical‐defined neuroendocrine differentiation and the detailed cytomorphologic features, clinicopathologic parameters, and prognosis of these tumors.
Background
Phyllodes tumors (PTs) of the breast are uncommon fibroepithelial neoplasms. Most behave in a benign fashion but they also have the potential to recur locally or to metastasize.
Methods
In ...the current study involving 290 PTs (181 benign, 76 borderline, and 33 malignant) from three hospitals over an 11-year period, we assessed the relationship between histologic parameters (including histologic features affecting grade and surgical margin status), postoperative adjuvant treatment, and local recurrences and distant metastases.
Results
An involved surgical margin was the only factor associated with increased risk of local recurrences (hazard ratio HR 4.673,
p
= 0.003), but not for distant metastases. For local recurrences, a wider margin did not confer additional benefits. None of the histologic factors were predictive for local recurrences. In contrast, distant metastases were correlated with histologic parameters, particularly an infiltrative border (HR 10.935,
p
= 0.012) and the presence of necrosis (HR 15.311,
p
= 0.007). In this series, all local recurrences were found in patients without radiotherapy, regardless of surgical margin status.
Conclusion
A negative surgical margin is mandatory for the effective local control of PT recurrence, and a minimal margin clearance may be sufficient. For distant metastases, the inherent characteristics of PTs are important, thus it may be prudent to evaluate additional histologic features, including necrosis, for patients’ prognostication.
Purpose
Clinical trials showing programmed death (PD)-1–PD-ligand 1 (L1) axis as a promising therapeutic target in melanoma and non-small cell lung cancers have made the pathway a focus of recent ...attention. However, the data regarding PD-L1/PD-1 in breast cancer are inconsistent. Given the heterogeneity of breast cancers, the clinical relevance of PD-L1 and PD-1 tumor infiltrating lymphocytes (TIL) may vary according to subtypes of breast cancer. We aim to investigate PD-L1 expression in a large cohort of breast cancers and analyze its clinico-pathological as well as outcome relationship according to molecular subtypes. Also, we evaluate the relationship of PD-1 TIL and PD-L1 expression with patients’ survival, particularly for breast cancers with high TIL.
Methods and results
Immunohistochemical analysis of PD-L1 on tissue arrays for 1091 breast cancer patients and PD-1 TIL on 97 whole sections was performed. Associations of PD-L1 with luminal cancers (
p
< 0.001) and features associated with that subtype lower histologic grade, absence of necrosis, ER, PR, and AR expression (
p
< 0.001) were observed. However, in HER2+ breast cancers, PD-L1 was an independent poor prognostic indicator (DFS: HR = 1.866,
p
= 0.001; OS: HR = 1.517,
p
= 0.036). Interestingly, HER2+ cancers showed a lower PD-1 TIL level compared to the other high TIL cases (
p
= 0.011). Cases with low PD-TIL but high PD-L1 expression showed the worst survival. This could be indicative of an active immune suppression by PD-L1 expression.
Conclusions
Our data showed the relevance of PD-L1 expression in HER2+ breast cancer. A combined evaluation of PD-L1 and PD-1 TIL in the prognosis of breast cancer might also be of value in treatment prediction.
Aims
Phyllodes tumours (PTs) of the breast are uncommon fibroepithelial neoplasms with the potential to recur and metastasise. Apart from histological grading, the expression of biological markers ...and its relationship with tumour behaviour have been topics of interest. The phosphatidylinositol 3‐kinase (PI3K)–AKT pathway regulates diverse biological functions, and is one of the most frequently deregulated pathways in cancers. Little is known of PI3K–AKT pathway alteration in PT. We aim to investigate the alterations in different component of AKT pathway in PTs.
Methods and results
This study investigated the expression of four biological markers involved in this pathway (PTEN, INPP4B, PI3KCA and pAKT) in 134 PTs by the use of immunohistochemistry. According to an immunoscore incorporating staining intensity and proportion, low epithelial INPP4B expression (P = 0.045) was associated with recurrence. A trend of association was found for low epithelial PTEN expression with recurrence (P = 0.090). Interestingly, low epithelial INPP4B expression was also associated recurred tumours (P = 0.043). Stromal PI3KCA expression (P = 0.016) and pAKT expression (P = 0.006) were found to be correlated with increased histological grade, but an opposite trend was seen for stromal INPP4B expression (P = 0.018). In addition, epithelial and stromal PTEN expression, PI3KCA expression and pAKT expression showed strong correlations with each other (P ≤ 0.001).
Conclusions
These findings indicate that alterations in AKT pathway activation may correlate with malignant transformation and recurrence in PT. Low epithelial INPP4B/PTEN expression is associated with shorter recurrence‐free survival. These observations suggest that the pathway may play a crucial role in the biological behaviour and progression of PT, and assessing the expression of this pathway may be of value in diagnosis, grading, prognostication, and management.
IgG4-related sclerosing disease is a distinctive mass-forming lesion with frequent systemic involvement, most frequently the pancreas, salivary glands, and lacrimal glands. This report describes a ...case manifesting with a previously unrecognized form of central nervous system involvement. The 37-year-old man presented with signs and symptoms of spinal cord compression at the thoracic level 9. Magnetic resonance imaging revealed an elongated dural mass extending from the fifth to tenth thoracic vertebra. Laminectomy and excision of the mass revealed dura expanded by a dense lymphoplasmacytic infiltrate accompanied by stromal fibrosis and phlebitis. IgG4+ plasma cells were increased and the proportion of IgG4+/IgG+ plasma cells was 85%. The patient also had a 1-year history of bilateral submandibular swelling due to chronic sialadenitis. Thus, IgG4-related sclerosing pachymeningitis represents a new member of the IgG4-related sclerosing disease family affecting the central nervous system. It seems that at least a proportion of cases described in the literature as idiopathic hypertrophic pachymeningitis belong to this disease, especially as some patients have other clinical manifestations compatible with IgG4-related sclerosing disease, such as cholangitis and orbital pseudotumor.
Background
β‐amyloid precursor protein (APP), a potential target for Alzheimer's disease treatment, has recently been shown to take part in carcinogenesis. Increased APP promotes migration, survival, ...and proliferation in breast cancer cell lines. We examined the clinical value of APP in breast cancers. A comprehensive examination of clinicopathological features related to APP expression in a large cohort of breast cancers and the corresponding metastatic lymph nodes was performed. APP expression and its prognostic impact in different breast cancer subtypes were examined.
Results
APP was highly expressed in nonluminal breast cancers and correlated with features associated with nonluminal breast cancers (including higher grade, the presence of necrosis, and higher proliferative index, growth factor receptor, and basal marker expression). Multivariate Cox hazard analysis demonstrated that APP was an independent adverse prognostic factor of disease‐free survival (DFS; hazard ratio HR, 2.090; p = .013; 95% confidence interval CI, 1.165–3.748) and breast cancer‐specific survival (BCSS; HR, 2.631; p = .002; 95% CI, 1.408–4.915) in the nonluminal group. The independent prognostic impact was also seen in triple negative breast cancers. Interestingly, a higher expression of APP was found in nodal metastasis compared with primary tumor. Such APP upregulation was correlated with further distal metastasis and poorer outcome (DFS: log‐rank, 12.848; p < .001; BCSS: log‐rank, 13.947; p < .001).
Conclusion
Our findings provided evidence of oncogenic roles of APP in clinical breast cancers. Patients with positive APP expression, particularly those with APP upregulation in lymph node metastases, may require vigilant monitoring of their disease and more aggressive therapy.
Implications for Practice
β‐amyloid precursor protein (APP), a potential target for Alzheimer's disease, has recently been implicated in oncogenesis. Here, evidence of its roles in clinical breast cancers is provided. Positive APP expression was found to be an independent prognostic factor in nonluminal cancers, particularly triple negative breast cancers (TNBCs). Interestingly, a higher APP in nodal metastases was associated with distal metastases. TNBCs are heterogeneous and currently have no available target therapy. APP could have therapeutic potential and be used to define the more aggressive cases in TNBCs. Current prognostic analysis is based on primary tumor. The present data suggest that investigation of nodal metastases could provide additional prognostic value.
摘要
背景。β‐淀粉样前体蛋白 (APP) 是阿尔茨海默病的潜在治疗靶点,最近已被证实参与肿瘤生成。APP 的增加促进了乳腺癌细胞系的迁移、存活和增殖。我们对 APP 在乳腺癌治疗中的临床价值进行了研究。我们对一个大型乳腺癌队列和相应的转移淋巴结中与 APP 表达相关的临床病理学特征进行了全面研究。并对 APP 表达及其对不同乳腺癌亚型的预后影响进行了研究。
结果。APP 在非管腔型乳腺癌中具有很高的表达率,并且与引起非管腔型乳腺癌的特征有关(包括等级更高、存在坏死及增殖指数更高,生长因子受体和基础标志物表达)。多变量 Cox 风险分析表明,APP 是无病生存期DFS;风险比 (HR),2.090;p = 0.013;95% 置信区间 (CI),1.165–3.748和非管腔型乳腺癌群体特异性生存期(BCSS;HR,2.631;p = 0.002;95% CI,1.408–4.915)的独立不良预后因素。在三阴性乳腺癌中也观察到了独立的预后因素。有趣的是,在淋巴结转移灶中发现了比原发性肿瘤更高的 APP 表达。这种 APP 的上调与进一步的远端转移和预后较差有关(DFS:log‐rank,12.848;p < 0.001;BCSS:log‐rank,13.947;p < 0.001)。
结论。我们的研究结果为 APP 在临床乳腺癌中具有致癌作用提供了证据。APP 阳性表达的患者,特别是淋巴结转移灶中 APP 上调的患者,可能需要谨慎监测病情并接受更积极的治疗。
对临床实践的提示: β‐淀粉样前体蛋白 (APP) 是阿尔茨海默病的潜在靶点,最近被证实参与肿瘤生成。在本研究中,我们为其在临床乳腺癌中发挥作用提供了证据。研究发现,APP 的阳性表达是非管腔型癌症,特别是三阴性乳腺癌 (TNBC) 的独立预后因子。有趣的是,淋巴结转移灶中 APP 的高表达与远端转移有关。TNBC 具有异质性,目前没有可用的靶向疗法。APP 具有治疗的潜力,可用于确定更具侵袭性的 TNBC 病例。目前的预后分析以原发肿瘤为基础。目前的数据表明,淋巴结转移的研究可以提供额外的预后价值。
This article assesses the expression of the α‐amyloid precursor protein (APP) in a large series of breast carcinomas and the corresponding metastatic lymph nodes.
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