Mesenchymal neoplasms with NTRK and other kinase gene alterations

Kinase alterations are increasingly recognised as oncogenic drivers in mesenchymal tumours. Infantile fibrosarcoma and the related renal tumour, congenital mesoblastic nephroma, were among the first solid tumours shown to harbour recurrent tyrosine kinase fusions, with the canonical ETV6::NTRK3 fusion identified more than 20 years ago. Although targeted testing has long been used in diagnosis, the advent of more robust sequencing techniques has driven the discovery of kinase alterations in an array of mesenchymal tumours. As our ability to identify these genetic alterations has improved, as has our recognition and understanding of the tumours that harbour these alterations. Specifically, this study will focus upon mesenchymal tumours harbouring NTRK or other kinase alterations, including tumours with an infantile fibrosarcoma-like appearance, spindle cell tumours resembling lipofibromatosis or peripheral nerve sheath tumours and those occurring in adults with a fibrosarcoma-like appearance. As publications describing the histology of these tumours increase so, too, do the variety kinase alterations reported, now including NTRK1/2/3, RET, MET, RAF1, BRAF, ALK, EGFR and ABL1 fusions or alterations. To date, these tumours appear locally aggressive and rarely metastatic, without a clear link between traditional features used in histological grading (e.g. mitotic activity, necrosis) and outcome. However, most of these tumours are amenable to new targeted therapies, making their recognition of both diagnostic and therapeutic import. The goal of this study is to review the clinicopathological features of tumours with NTRK and other tyrosine kinase alterations, discuss the most common differential diagnoses and provide recommendations for molecular confirmation with associated treatment implications.     

何首乌致药物性肝损伤的病理学特点

目的了解何首乌致药物性肝损伤(Polygonum multiflorum-associated drug induce liver injury,PM-DILI)的临床病理学特点。方法收集2019年3月1日至2021年3月1日深圳市第三人民医院收治的8例PM-DILI患者临床资料。肝穿组织进行苏木素-伊红染色、网状纤维染色、Masson三色染色、铁、铜特殊染色和免疫组织化学染色,显微镜下观察分析。结果8例PM-DILI患者男女比为1∶1,平均年龄43岁,其中6例为急性PM-DILI,2例慢性为PM-DILI。入院血清学检查异常主要包括转氨酶升高和淤胆均为7例。主要组织病理学改变为点灶状坏死8例、界面炎5例、融合坏死4例,融合坏死以肝腺泡3带为主,不伴或伴少数炎细胞浸润;胆汁淤积5例,为肝腺泡3带的肝细胞、毛细胆管内淤胆,不伴或伴少数炎细胞浸润;中央静脉炎3例;病程长者可发生肝纤维化,甚至肝硬化2例。结论肝腺泡3带为主的急性淤胆和肝细胞坏死是PM-DILI主要组织学表现,严重者可发生静脉炎等血管损伤。     

Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.