Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified ...into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent
mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in
promoter and
A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours:
,
, and
.
Aims
Breast phyllodes tumours (PTs) are a rare subset of fibroepithelial neoplasms categorised into benign, borderline, and malignant grades according to the World Health Organization (WHO) ...Classification of Tumours (WCTs). In this report, we developed an evidence gap map (EGM) based on the literature cited in the PT chapter of the 5th edition of the breast WCT in order to identify knowledge and research gaps in PT.
Methods
A framework was first established where the dimensions of the EGM were defined as categories of tumour descriptors, tumour types, and evidence levels. Citations were collected into a Microsoft Excel form and imported into EPPI‐reviewer to produce the EGM.
Results
The EGM showed that the “Histopathology” and “Pathogenesis” sections contained the most citations, the majority being of low‐level evidence. The highest number of citations considered of moderate‐level evidence were found in the “Histopathology” section. There was no high‐level evidence cited in this chapter. The “Localisation”, “Aetiology”, and “Staging” sections had the fewest citations.
Conclusion
This EGM provides a visual representation of the cited literature in the PT chapter of the breast WCT, revealing the lack of high‐level evidence citations. There is an uneven distribution of references, probably due to citation practices. Pockets of low‐level evidence are highlighted, possibly related to referencing habits, lack of relevant research, or the belief that the information presented is standard accepted fact, without the need for specific citations. Future work needs to bridge evidence gaps and broaden citations beyond those in the latest WCT.
Number of publications according to their evidence type and level of evidence, in the PT chapter of the WHO classification of tumours of the breast (5th edition).
Immune response can affect tumour progression and treatment outcome. This study investigated the potential of stromal macrophages around ductal carcinoma in situ (DCIS) in predicting recurrence and ...progression. CD68 and CD163 expression of macrophages in DCIS from 198 patients was determined by immunohistochemistry. Disease free survival (DFS), clinicopathological parameters and biomarker expression were correlated with the densities of both CD68
+
and CD163
+
macrophages. High CD68
+
macrophage density was associated with high nuclear grade (
p
< 0.001), oestrogen receptor (ER) negativity (
p
= 0.029), progesterone receptor (PR) negativity (
p
= 0.008) and human epidermal growth factor receptor 2 (HER2) positivity (
p
< 0.001). High CD163
+
macrophage density was associated with high nuclear grade (
p
= 0.003), microinvasion (
p
= 0.01), ER negativity (
p
< 0.001), PR negativity (
p
= 0.001), HER2 positivity (
p
= 0.001) and triple negativity (
p
= 0.022). DCIS with higher CD68
+
macrophage density disclosed significantly worse DFS for ipsilateral invasive recurrence (
p
= 0.004) and is affirmed by multivariate Cox regression analysis (95% CI 1.126–5.102, HR = 2.397,
p
= 0.023). DCIS with higher CD163
+
macrophage density showed significantly worse DFS for both recurrence (
p
= 0.001) and ipsilateral invasive recurrence (
p
= 0.001). These findings, for CD163
+
macrophage density, were affirmed by multivariate Cox regression analysis respectively for both recurrence (95% CI 1.210–2.293, HR = 1.880,
p
= 0.005) and ipsilateral invasive recurrence (95% CI 1.122–5.176, HR = 2.410,
p
= 0.024). This study demonstrated that DCIS with higher macrophage density was associated with poorer prognostic parameters, while DCIS with higher CD163
+
macrophage density predicted both recurrence and ipsilateral invasive recurrence.
Breast fibroepithelial lesions (FELs) encompass the common fibroadenoma (FA) and relatively rare phyllodes tumour (PT); the latter entity is usually classified as benign, borderline or malignant. ...Intratumoural heterogeneity is frequently present in these tumours, making accurate histologic evaluation challenging. Despite their rarity, PTs are an important clinical problem due to their propensity for recurrence and, in the case of malignant PT, metastasis. Surgical excision is the mainstay of management. Recent work has uncovered myriad genetic alterations in breast FELs. In this study, exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including FAs, PTs of all grades, and a case of metaplastic spindle cell carcinoma arising in PT, in order to elucidate their intratumoural genetic repertoire. Gene mutations identified encompassed cell signalling, tumour suppressor, DNA repair and cell cycle regulating pathways. Mutations common to multiple tumour regions generally showed higher variant allele frequency. Frequent mutations included MED12, TP53, RARA and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumour progression. In summary, histological heterogeneity correlated with genetic changes in breast FELs.
The hierarchy of evidence is a fundamental concept in evidence-based medicine, but existing models can be challenging to apply in laboratory-based health care disciplines, such as pathology, where ...the types of evidence and contexts are significantly different from interventional medicine. This project aimed to define a comprehensive and complementary framework of new levels of evidence for evaluating research in tumor pathology-introducing a novel Hierarchy of Research Evidence for Tumor Pathology collaboratively designed by pathologists with help from epidemiologists, public health professionals, oncologists, and scientists, specifically tailored for use by pathologists-and to aid in the production of the World Health Organization Classification of Tumors (WCT) evidence gap maps. To achieve this, we adopted a modified Delphi approach, encompassing iterative online surveys, expert oversight, and external peer review, to establish the criteria for evidence in tumor pathology, determine the optimal structure for the new hierarchy, and ascertain the levels of confidence for each type of evidence. Over a span of 4 months and 3 survey rounds, we collected 1104 survey responses, culminating in a 3-day hybrid meeting in 2023, where a new hierarchy was unanimously agreed upon. The hierarchy is organized into 5 research theme groupings closely aligned with the subheadings of the WCT, and it consists of 5 levels of evidence-level P1 representing evidence types that merit the greatest level of confidence and level P5 reflecting the greatest risk of bias. For the first time, an international collaboration of pathology experts, supported by the International Agency for Research on Cancer, has successfully united to establish a standardized approach for evaluating evidence in tumor pathology. We intend to implement this novel Hierarchy of Research Evidence for Tumor Pathology to map the available evidence, thereby enriching and informing the WCT effectively.
To determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes.
Phyllodes tumours ...from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out.
There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015).
Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms.
Genetics and genomics of breast fibroadenomas Loke, Benjamin Nathanael; Md Nasir, Nur Diyana; Thike, Aye Aye ...
Journal of clinical pathology,
05/2018, Letnik:
71, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Fibroadenomas of the breast are benign fibroepithelial tumours most frequently encountered in women of reproductive age, although they may be diagnosed at any age. The fibroadenoma comprises a ...proliferation of both stromal and epithelial components. The mechanisms underlying fibroadenoma pathogenesis remain incompletely understood. In the clinical setting, distinguishing cellular fibroadenomas from benign phyllodes tumours is a common diagnostic challenge due to subjective histopathological criteria and interobserver differences. Recent sequencing studies have demonstrated the presence of highly recurrent mutations in fibroadenomas, and also delineated the genomic landscapes of fibroadenomas and the closely related phyllodes tumours, revealing differences at the gene level, which may be of potential adjunctive diagnostic use. The present article provides an overview of key studies uncovering genetic and genomic abnormalities in fibroadenomas, from initial karyotype reports revealing myriad cytogenetic aberrations to next-generation sequencing-based approaches that led to the discovery of highly recurrent
mutations. A thorough understanding of these abnormalities is important to further elucidate the mechanisms by which fibroadenomas arise and to refine diagnostic assessment of this very common tumour.
Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in ...MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.
Characterising the factors responsible for metastatic triple-negative breast cancer (TNBC) is of significant importance, considering its high mortality rate and scant data. In this study, we ...evaluated the characteristics, clinical behaviour and role of biomarkers (androgen receptor (AR), oestrogen receptor beta (ERβ) and p53) in metastatic TNBC.
Immunohistochemistry was performed for AR, ERβ and p53 on 125 primary TNBCs with known metastasis and correlated with clinicopathological parameters and outcome.
and
mRNA profiling was also carried out on 34 tumours from the same series and correlated with outcomes.
In this cohort, grade 3 and pT2 tumours predominated. The most common site for metastasis was the lung and pleura (41, 32.8%), and 15 (12.0%) cases demonstrated metastasis in multiple sites. Among these, 92% of tumours metastasised without preceding local recurrences. Five- and ten-year overall survival (OS) rates were 27% and 7.2%, while 5- and 10- year survival rates after metastasis were 9.6% and 3.2% respectively. AR, ERβ and p53 protein expressions were observed in 16%, 96.8% and 58.1% of tumours, respectively. A combinational phenotype of AR-ERβ+p53+ tumours was associated with poorer OS (HR 1.543, 95%CI 1.030 to 2.310, p=0.035). Higher
mRNA levels were significantly associated with favourable OS (p=0.015) and survival after metastasis (p=0.027).
Metastatic TNBC harboured aggressive behaviour and displayed predominantly visceral metastasis with most metastatic events occurring without intervening local recurrences. A combinational phenotype of AR-ERβ+p53+ was significantly associated with poorer OS.
Breast fibroepithelial lesions (FEL) are biphasic tumors which consist of benign fibroadenomas (FAs) and the rarer phyllodes tumors (PTs). FAs and PTs have overlapping features, but have different ...clinical management, which makes correct core biopsy diagnosis important. This study used whole-slide images (WSIs) of 187 FA and 100 PT core biopsies, to investigate the potential role of artificial intelligence (AI) in FEL diagnosis. A total of 9228 FA patches and 6443 PT patches was generated from WSIs of the training subset, with each patch being 224 × 224 pixel in size. Our model employed a two-stage architecture comprising a convolutional neural network (CNN) component for feature extraction from the patches, and a recurrent neural network (RNN) component for whole-slide classification using activation values from the global average pooling layer in the CNN model. It achieved an overall slide-level accuracy of 87.5%, with accuracies of 80% and 95% for FA and PT slides respectively. This affirms the potential role of AI in diagnostic discrimination between FA and PT on core biopsies which may be further refined for use in routine practice.
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