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Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

Obesity is a remarkably important factor for breast carcinogenesis and aggressiveness. The implication of increased BMI in triple negative breast cancer (TNBC) development is also well established. A malignancy-promoting role of the adipose tissue has been supposed, where the adipocytes that constitute the majority of stromal cells release pro-inflammatory cytokines and growth factors. Alterations in adipokines and their receptors play significant roles in breast cancer initiation, progression, metastasis, and drug response. Classic adipokines, such as leptin, adiponectin, and resistin, have been extensively studied in breast cancer and connected with breast cancer risk and progression. Notably, new molecules are constantly being discovered and the list is continuously growing. Additionally, substantial progress has been made concerning their differential expression in association with clinical and pathological parameters of tumors and the prognostic and predictive value of their dysregulation in breast cancer carcinogenesis. However, evidence regarding the mechanisms by which adipose tissue is involved in the development of TNBC is lacking. In the present article we comment on current data on the suggested involvement of these mediators in breast cancer development and progression, with particular emphasis on TNBC, to draw attention to the design of novel targeted therapies and biomarkers.

Prostate cancer is the second most common malignancy in men, and prostatectomy is the treatment of choice for most patients with at least low risk of progression. The presence of positive margins in the radical prostatectomy specimen is considered an adverse pathologic feature, and may prompt additional therapeutic intervention in the patients. The absence of a distinct capsule around the prostate and intraoperative manipulations that aim to minimize postoperative adverse effects, complicate its wide removal. Proper handling of the specimen during the gross processing is essential for accurate determination of the status of margins or resection. Positive margins, defined as the presence of neoplastic glands in the highlighted-with-ink margin of resection, range from 6-38%. The surgical technique, surgeon's expertise and tumor (i.e., grade and stage) and patients' (i.e., BMI) characteristics affect the rate of margin positivity. Extensive or multifocal and nonanterior/nonapical positive margins are linked with higher recurrence rates, especially in organ-confined disease, underscoring the need for treating these patients more aggressively. In summary, detailed description of the status of the margins should be performed in every pathology report to determine patients' prognosis and the most appropriate therapeutic plan.

(1) Background: Prognostic grade group (PGG) is an important prognostic parameter in prostate cancer that guides therapeutic decisions. The cribriform pattern and intraductal carcinoma (IDC) are two histological patterns, that have additional prognostic significance. However, discrepancies exist regarding the handling of IDC according to the guidelines published by two international genitourinary pathology societies. Furthermore, whether, in addition to its presence, the amount of IDC is also of importance has not been studied before. Lastly, the handling of tertiary patterns has also been a matter of debate in the literature. (2) Methods: A total of 129 prostatectomy cases were retrieved and a detailed histopathologic analysis was performed. (3) Results: Two cases (1.6%) upgraded their PGG, when IDC was incorporated in the grading system. The presence and the amount of IDC, as well as the presence of cribriform carcinoma were associated with adverse pathologic characteristics. Interestingly, in six cases (4.7%) there was a difference in PGG when using the different guidelines regarding the handling of tertiary patterns. In total, 6.2% of the cases would be assigned a different grade depending on the guidelines followed. (4) Conclusions: These findings highlight a potential area of confusion among pathologists and clinicians and underscore the need for a consensus grading system.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539-0.735, p < 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727-0.864, p < 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561-0.756, p < 0.001) and 40% (ICC 0.644, 95% CI 0.546-0.745, p < 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.

Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer characterized by genomic complexity and therapeutic options limited to only standard chemotherapy. Although it has been suggested that stratifying TNBC patients by pathway-specific molecular alterations may predict benefit from specific therapeutic agents, application in routine clinical practice has not yet been established. There is a growing body of the literature supporting that epigenetic modifications comprised by DNA methylation, chromatin remodeling and non-coding RNAs play a fundamental role in TNBC pathogenesis. Extracellular matrix (ECM) is a highly dynamic 3D network of macromolecules with structural and cellular regulatory roles. Alterations in the expression of ECM components result in uncontrolled matrix remodeling, thus affecting its ability to regulate vital functions of cancer cells, including proliferation, migration, adhesion, invasion and epithelial-to-mesenchymal transition (EMT). Recent molecular data highlight the major role of tumor microenvironment and ECM alterations in TNBC and approaches for targeting tumor microenvironment have recently been recognized as potential therapeutic strategies. Notably, many of the ECM/EMT modifications in cancer are largely driven by epigenetic events, highlighting the pleiotropic effects of the epigenetic network in TNBC. This article presents and critically discusses the current knowledge on the epigenetic alterations correlated with TNBC pathogenesis, with emphasis on those associated with ECM/EMT modifications, their prognostic and predictive value and their use as therapeutic targets., Competing Interests: The authors declare no conflict of interest.