Molecular Testing in Ovarian Tumours: Challenges from the Pathologist's Perspective.

The use of molecular testing to direct diagnosis and treatment options in ovarian tumours has rapidly expanded in recent years, in particular with regard to the recommendation for routine homologous recombination deficiency (HRD) testing in all patients with high-grade ovarian epithelial tumours. The implications of this increased level of testing upon the pathologist is significant in terms of increased workload, the provision of adequate tumour samples for molecular testing, and the interpretation of complex molecular pathology reports. In order to optimise the quality of reports generated, it is important to establish clear pathways of communication on both a local and national level between clinicians, pathology lab staff, and medical scientists. On a national level, in the United Kingdom, Genomic Laboratory Hubs (GLHs) have been established to provide a uniform high-quality molecular diagnostics service to all patients with ovarian tumours within the National Health services in the country. On a local level, there are a number of small steps that can be taken to improve the quality of tissues available for testing and to streamline the processes involved in generating requests for molecular testing. This article discusses these factors from the perspective of the clinical histopathologist.

A case of adrenal Cushing's syndrome and primary hyperparathyroidism due to an atypical parathyroid adenoma.

Cushing's syndrome is a rare disorder of cortisol excess and is associated with significant morbidity and mortality. Hypercalcaemia due to hyperparathyroidism is a common condition; however, in 10% of young patients, it is associated with other endocrinopathies and occurs due to a genetic variant [e.g. multiple endocrine neoplasia (MEN) type 1 (MEN1), MEN2 or MEN4]. We report the case of a 31-year-old woman who was referred to the endocrinology out-patient service with an 8-month history of hirsutism, amenorrhoea and weight gain. Her biochemical work up was significant for adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome. Radiological investigations revealed an adrenal adenoma. During investigation she was also found to have primary hyperparathyroidism due to a parathyroid adenoma. Pre-operatively, the patient was commenced on metyrapone and both her adrenal and parathyroid lesions were resected successfully. There were several concerning findings on initial examination of the parathyroid tumour, including possible extension of the tumour through the capsule and vascular invasion; however, following extensive review, it was ultimately defined as an adenoma. Given the unusual presence of two endocrinopathies in a young patient, she subsequently underwent genetic testing. Analysis of multiple genes did not reveal any pathogenic variants. The patient is currently clinically well, with a normal adjusted calcium and no clinical features of cortisol excess. She will require long-term follow up for recurrence of both hypercalcaemia and hypercortisolaemia.

The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma.

Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.

Linking Circulating Serum Proteins with Clinical Outcomes in Esophageal Adenocarcinoma-An Emerging Role for Chemokines.

Esophageal adenocarcinoma (EAC) is an aggressive cancer with poor prognosis and incidence is increasing rapidly in the Western world. Multi-modal treatment has improved survival outcomes but only for a minority of patients. Currently no markers have been identified to predict treatment response. This study investigated the association between clinical outcomes and pre-treatment levels of 54 serum proteins in n = 80 patients with EAC. Low tumor regression grade (TRG), corresponding to a favorable treatment response, was linked to prolonged overall survival (OS). CCL4 was higher in patients with a favorable treatment response, while Tie2 and CRP were higher in poor responders. Elevated CCL22 and CCL26 was associated with improved OS, while elevated IL-10 showed a negative association. CCL3, CCL4, IL-1α and IL-12/IL23p40 were highest in individuals with no adverse features of tumor biology, whereas levels of Tie2 and VEGF were lowest in this cohort. CCL4 was also elevated in patients with high tumor lymphocyte infiltration. Comparison of matched pre- and post-treatment serum (n = 28) showed a large reduction in VEGFC, and a concomitant increase in other cytokines, including CCL4. These data link several serum markers with clinical outcomes, highlighting an important role for immune cell trafficking in the EAC antitumor immune response.

Impact and importance of a centralised review panel for lymphoma diagnostics in the WHO era: a single-centre experience.

Lymphoma diagnosis is complex, requiring a wide array of adjunctive tests to reach accurate diagnoses. We retrospectively examined the rates of concordance between referral and review lymphoma diagnoses on cases referred to St James's Hospital, Dublin for multidisciplinary team review between 2013 and 2016. Frequency and cost of adjunctive diagnostic tests performed were also analysed. The overall discordance rate was 7.8% (14/179), compared with rates of 6%-48% in the published literature. 13 discordant cases required a change in clinical management following review of the referred diagnosis. Of all referred cases, 33.5% (60/179) required extra analyses to reach a final diagnosis, costing the reference laboratory €35463.40. We conclude that establishment of centralised haematopathology diagnostic networks would help reduce the rate of revision made to lymphoma diagnoses by providing specialist haematopathologist input and access to ancillary testing.

Evaluation of hemodynamically severe coronary stenosis as determined by fractional flow reserve with frequency domain optical coherence tomography measured anatomical parameters.

OBJECTIVES: The main objective of this study is to determine the correlation between fractional flow reserve (FFR)- and frequency domain optical coherence tomography (FD-OCT)-measured lumen parameters, and to determine the diagnostic competence of FD-OCT concerning the identification of severe coronary stenosis. METHODS: A total of 41 coronary stenoses in 30 patients were assessed consecutively by quantitative coronary angiography (QCA), FFR, and FD-OCT. Stenoses were labeled severe if FFR ≤ 0.80. The minimal lumen area (MLA), minimal lumen diameter (MLD), and percent lumen area stenosis (%AS) were measured using FD-OCT. RESULTS: FFR was ≤ 0.80 in 10 stenoses (24.4%). A poor but significant correlation between FFR and FD-OCT-measured MLA (r(2) = 0.4, p < 0.001), MLD (r(2) = 0.28, p < 0.001), and %AS (r(2) = 0.13, p = 0.02) was found. In the overall group, the diagnostic efficiency of MLA and MLD in identifying significant stenosis was moderate. The area under the curve (AUC) was 0.80 [95% confidence interval (CI): 0.64-0.91] for MLA and 0.76 (95% CI: 0.60-0.88) for MLD. The best cut-off values of FD-OCT-measured lumen parameters to identify stenosis with FFR ≤ 0.80 were 1.62 mm(2) [specificity 97%, sensitivity 70%, positive predictive value (PPV) 89% and negative predictive value (NPV) 91%] for MLA and 1.23 mm (specificity 87%, sensitivity 70%, PPV 64% and NPV 90%) for MLD. The diagnostic efficiency of MLA in identifying significant stenosis in vessels having reference diameter < 3 mm was high. The AUC was 0.96 (95% CI: 0.83-1.0). CONCLUSIONS: The FFR values and FD-OCT anatomical parameters MLA, MLD were found to be significantly correlated. In the overall group, the FD-OCT-measured MLA and MLD have shown moderate diagnostic efficiency in the functional evaluation of significant stenosis. FD-OCT-measured MLA has high diagnostic efficiency in identifying severe coronary stenosis in vessels having reference diameter < 3 mm.

Prognostic significance of deregulated dicer expression in breast cancer.

BACKGROUND: Dicer, an RNase III-type endonuclease, is the key enzyme involved in RNA interference and microRNA pathways. Aberrant expression of Dicer is reported in several human cancers. Our aim was to assess the prognostic role of Dicer in breast cancer. METHODS: The entire series comprised 666 invasive breast cancers (IBCs), 480 DCIS cases (397 associated with IBC and 83 pure DCIS) and 305 lymph node metastases. Cytoplasmic Dicer expression by immunohistochemistry was scored as negative (no staining) and positive (weak, moderate or strong staining). RESULTS: Dicer staining was assessable in 446 IBC, 128 DCIS and 101 lymph node metastases. Expression of Dicer was observed in 33% (145/446) of IBCs, 34% (44/128) of DCIS and 57% (58/101) of lymph node metastases. Dicer expression was increased in nodal metastases compared to primary tumours (p<0.001); and was associated with ER negativity (p<0.001), HER2 positivity (p<0.001), high Ki67 labeling index (p<0.001) and expression of basal-like biomarkers (p = 0.002). Dicer positivity was more frequent in the HER2 overexpressing (p<0.001) and basal-like (p = 0.002) subtypes compared to luminal A subtype. Dicer expression was associated with reduced overall survival (OS) on univariate analysis (p = 0.058) and remained an independent predictor of OS on multivariate analysis (HR 2.84, 95% CI 1.43-5.62, p = 0.003), with nodal status (HR 2.61, 95% CI 1.18-5.80, p = 0.018) and PR (HR 0.28, 95% CI 0.13-0.59, p = 0.001). Further, moderate or strong expression of Dicer was associated with improved disease-free survival in the HER2-overexpressing subtype compared to negative or weak expression (p = 0.038). CONCLUSION: Deregulated Dicer expression is associated with aggressive tumour characteristics and is an independent prognostic factor for OS. Our findings suggest that Dicer is an important prognostic marker in breast cancer and that its prognostic role may be subtype specific.