J. Mol. Pathol., Volume 2, Issue 4 (December 2021) – 5 articles

Breast cancer is the most common cause of cancer-related deaths in the female population worldwide. To the best of our knowledge, breast cancer (BRCA)1/2 gene mutations have not been described yet on breast cancer cytological specimens. Here we describe the case of a 38-year old woman with a family and personal history for breast cancer, who underwent a fine needle aspiration (FNA) procedure for a novel 30 mm lesion located in the external quadrants of the contralateral (left) breast. Cytological findings and ancillary immunostaining confirmed the diagnosis of a triple negative NST carcinoma. BRCA1/2 molecular assessment was carried out on DNA extracted from cytological (November 2020), biopsy (December 2014) and surgical resection (July 2015) specimens, as well as on the resection of a benign fibroadenoma, by using a next generation sequencing approach. Molecular analysis showed a pathogenic BRCA1 insertion (c.5266dupC; p.Q1756PfsTer74) in the cytological specimen (allelic fraction 92.0%), biopsy (allelic fraction 84.2%), surgical resection (allelic fraction 87.8%) and fibroadenoma (58.9%), demonstrating a germinal BRCA mutated status. Full article

Given the increase in genomic testing in routine clinical use, there is a growing need for digital technology solutions to assist pathologists, oncologists, and researchers in translating variant calls into actionable knowledge to personalize patient management plans. In this article, we discuss the challenges facing molecular geneticists and medical oncologists in working with test results from next-generation sequencing for somatic oncology, and propose key considerations for implementing a decision support software to aid the interpretation of clinically important variants. In addition, we review results from an example decision support software, NAVIFY Mutation Profiler. NAVIFY Mutation Profiler is a cloud-based software that provides curation, annotation, interpretation, and reporting of somatic variants identified by next-generation sequencing. The software reports a tiered classification based on consensus recommendations from AMP, ASCO, CAP, and ACMG. Studies with NAVIFY Mutation Profiler demonstrated that the software provided timely updates and accurate curation, as well as interpretation of variant combinations, demonstrating that decision support tools can help advance implementation of precision oncology. Full article

Well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumour (WDPMT) in the current WHO classification because all mesotheliomas are now regarded as malignant. WDPMT is now defined as a non-invasive papillary mesothelial proliferation, with retained labelling for BAP1-desirable. The current WHO classification also includes mesothelioma in situ (MIS), which is defined as pre-invasive flat or papillary proliferation of mesothelial cells with a loss of BAP1 or MTAP. WDPMT has been variably defined in the past but was thought to occur more commonly in women and pursue a more indolent course than mesothelioma, but its progression to invasive disease has occasionally been reported. Here, we report a case of a 68-year-old woman with a history of asbestos exposure and an underlying diagnosis of Ehlers Danlos syndrome who was diagnosed with symptomatic WDPMT of the peritoneum that progressed to mesothelioma within two years. On retrospective analysis, the WDPMT showed a loss of BAP1. We suggest that a loss of BAP1 in WDPMT should be reported, since these lesions may show aggressive behaviour, and that they may best be regarded as similar to mesothelioma in situ. Full article

Introduction: In recent years, there has been a growing development of molecularly targeted therapies for various types of solid tumors—in particular, in non-small-cell lung cancer (NSCLC). This has required the need for greater quantities of tissue that is able to support ancillary studies, alongside cyto-histological diagnoses for the assessment of molecular targets. Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) have shown a high diagnostic yield for malignant mediastinal and/or hilar lymph node enlargement and peribronchial masses; however, few studies have compared these two procedures. We retrospectively compared TBNA patients (EBUS-TBNA and cTBNA) in order to determine the diagnostic yield and material adequacy for subsequent ancillary analyses. Materials and Methods: We retrospectively evaluated 318 patients with clinical suspicion of lung cancer or with disease recurrence. All of the patients underwent TBNA (either EBUS-TBNA or cTBNA) on enlarged mediastinal and/or hilar lymph nodes and peribronchial masses between January 2017 and June 2021 at the University Hospital of Pisa, Italy. After a definitive diagnosis, molecular analyses and an evaluation of PD-L1 expression were performed in the cases of adenocarcinoma, squamous cell carcinoma, and NSCLC, not otherwise specified (NOS). Results: EBUS-TBNA was performed in 199 patients and cTBNA was performed in 119 patients with 374 and 142 lymph nodes, respectively. The overall diagnostic yield for positive diagnoses was 59% (diagnostic rate of 61% in EBUS-TBNA, and 55% in cTBNA). Adenocarcinoma (ADC) was the most frequent diagnosis in both methods. EBUS-TBNA diagnostic adequacy was 72% for molecular analysis, while it was 55.5% for cTBNA, showing a statistical trend (p = 0.08) towards the significance of EBUS. The average percentage of neoplastic cells was also statistically different between the two methods (p = 0.05), reaching 51.19 ± 22.14 in EBUS-TBNA and 45.25 ± 22.84 in cTBNA. With regard to the PD-L1 protein expression, the percentage of positivity was similar in both procedures (86% in EBUS-TBNA, 85% in cTBNA). Conclusions: Conventional TBNA (cTBNA) and EBUS-guided TBNA (EBUS-TBNA) are minimally invasive diagnostic methods that are associated with a high diagnostic yield. However, EBUS-TBNA has an improved diagnostic adequacy for molecular analysis compared to cTBNA, and is associated with a higher average percentage of neoplastic cells. Full article

Centromeric proteins are the foundation for assembling the kinetochore, a macromolecular complex that is essential for accurate chromosome segregation during mitosis. Anti-centromere antibodies (ACAs) are polyclonal autoantibodies targeting centromeric proteins (CENP-A, CENP-B, CENP-C), predominantly CENP-B, and are highly associated with rheumatologic disease (lcSSc/CREST syndrome). CENP-B autoantibodies have also been reported in cancer patients without symptoms of rheumatologic disease. The rise of oncoimmunotherapy stimulates inquiry into how and why anti-CENP-B autoantibodies are formed. In this review, we describe the clinical correlations between anti-CENP-B autoantibodies, rheumatologic disease, and cancer; the molecular features of CENP-B; possible explanations for autoantigenicity; and, finally, a possible mechanism for induction of autoantibody formation. Full article