Pathogenesis and therapeutic implications of EBV-associated epithelial cancers.

Epstein-Barr virus (EBV), one of the most common human viruses, has been associated with both lymphoid and epithelial cancers. Undifferentiated nasopharyngeal carcinoma (NPC), EBV associated gastric cancer (EBVaGC) and lymphoepithelioma-like carcinoma (LELC) are amongst the few common epithelial cancers that EBV has been associated with. The pathogenesis of EBV-associated NPC has been well described, however, the same cannot be said for primary pulmonary LELC (PPLELC) owing to the rarity of the cancer. In this review, we outline the pathogenesis of EBV-associated NPC and EBVaGCs and their recent advances. By drawing on similarities between NPC and PPLELC, we then also postulated the pathogenesis of PPLELC. A deeper understanding about the pathogenesis of EBV enables us to postulate the pathogenesis of other EBV associated cancers such as PPLELC.

The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers.

Microsatellite-instability-high (MSI-H) cancers form a spectrum of solid organ tumors collectively known as Lynch Syndrome cancers, occurring not only in a subset of colorectal, endometrial, small bowel, gastric, pancreatic, and biliary tract cancers but also in prostate, breast, bladder, and thyroid cancers. Patients with Lynch Syndrome harbor germline mutations in mismatch repair genes, with a high degree of genomic instability, leading to somatic hypermutations and, therefore, oncogenesis and cancer progression. MSI-H cancers have unique clinicopathological characteristics compared to their microsatellite-stable (MSS) counterparts, marked by a higher neoantigen load, immune cell infiltration, and a marked clinical response to immune checkpoint blockade. Patients with known Lynch Syndrome may be detected early through surveillance, but some patients present with disseminated metastatic disease. The treatment landscape of MSI-H cancers, especially colorectal cancers, has undergone a paradigm shift and remains to be defined, with immune checkpoint blockade coming to the forefront of treatment strategies in the stage IV setting. We summarize in this review the clinical features of MSI-H cancers with a specific interest in the pattern of spread or recurrence, disease trajectory, and treatment strategies. We also summarize the tumor-immune landscape and genomic profile of MSI-H cancers and potential novel therapeutic strategies.