Frequency of discordance in programmed death-ligand 1 (PD-L1) expression between primary tumors and paired distant metastases in advanced cancers: a systematic review and meta-analysis.

Background: To determine the frequency of discordance in programmed death-ligand 1(PD-L1) expression between primary tumors and paired distant metastases in advanced cancers.Methods: We searched MEDLINE and EMBASE for eligible studies and assessed their methodologic quality using QUADAS-2 tool. We estimated the discordant rates (positive to negative or vice versa) of PD-L1 expression in primary tumors and paired distant metastases using logistic-normal random effects model. We performed subgroup analyses based on the PD-L1 status of primary tumors (positive or negative), location of primary tumors (lung or others) and distant metastases (central nervous system or others), timing of distant metastases (synchronous or metachronous), positivity thresholds of PD-L1 expression (1% or 5%) and types of antibody clones used (E1L3N or SP142).Results: Thirteen eligible studies including 451 cases were identified. The included studies were judged to have low to unclear risk of bias. The pooled estimate of discordant rates in PD-L1 expression was 31% (95% CI= 19-47%), with high heterogeneity across the studies (I2 = 75%). There was no significant effect modification in the discordant rates according to the predefined subgroups.Conclusion: Approximately one-third of advanced cancer cases have discordance in PD-L1 expression between primary tumors and paired distant metastases. A more liberal testing of PD-L1 expression in both primary and metastatic tumors is recommended in order to identify patients who may benefit from immune checkpoint blockade treatment. Further research exploring the mechanisms and its impact are warranted.

Thyroid cytology-nuclear versus architectural atypia within the "Atypia of undetermined significance/follicular lesion of undetermined significance" Bethesda category have significantly different rates of malignancy.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is the most widely used classification system for the reporting of thyroid fine-needle aspiration cytology (FNAC) specimens. However, the "atypical" category ("atypia of undetermined significance" [AUS] or "follicular lesion of undetermined significance" [FLUS]) continues to cause diagnostic and therapeutic dilemmas. The objectives of this study were to describe the differential malignancy rates of FNACs diagnosed as AUS/FLUS based on nuclear or architectural atypia and to assess the significance of demographic and ultrasonographic features in predicting malignancy in this category. METHODS: A retrospective review was performed of all thyroid FNACs between 2008 and 2014 that were diagnosed as AUS/FLUS at a tertiary referral center in Singapore. Patient demographics, preoperative ultrasonographic features, and follow-up data were collected and correlated with the final histopathologic diagnosis in resected cases. RESULTS: In total, 309 thyroid nodules were diagnosed as AUS/FLUS, and 137 (44%) were surgically excised. Final histology yielded 37 (27%) malignancies. The malignancy rate for nodules that featured nuclear atypia was significantly higher at 36.8% than the rate for nodules that had only architectural atypia at 14.7% (P < .01). After up to 3 repeat FNACs, 67.1% of cases had a more definitive diagnosis. The only predictive sonographic finding for malignancy was irregular margins (P < .01). CONCLUSIONS: The disparity between malignancy risks within the Bethesda "atypical" category suggests that cytologic (nuclear) atypia is significantly more predictive of malignancy than architectural atypia. This supports the substratification of patients according to risk and a corresponding management approach within this category. A sonographic finding of irregular margins is also predictive for malignancy. Cancer Cytopathol 2017;125:245-256. © 2016 American Cancer Society.

From epistaxis to bone pain-report of two cases illustrating the clinicopathological spectrum of phosphaturic mesenchymal tumour with fibroblast growth factor receptor 1 immunohistochemical and cytogenetic analyses.

AIMS: Phosphaturic mesenchymal tumour (PMT) is a rare, recently described neoplastic entity. It is characterized by distinct histological features, which often occur together with oncogenic osteomalacia. Recently, a novel FN1-FGFR1 gene fusion has been described in a subset of PMTs. The aim of this study is to characterise the clinicopathological features of two PMTs, with FGFR1 immunohistochemical and cytogenetic analyses. METHODS AND RESULTS: We present two contrasting cases of PMT, one occurring in the sinonasal region, and the other occurring in bone (proximal femur). In the former, local effects, including epistaxis and anosmia, dominated the clinical presentation, whereas the latter case presented with refractory bone pain, muscle weakness, and occult osteomalacia, the cause of which was only identified after 2 years. Both tumours showed characteristic histological features of PMT, including a monomorphic proliferation of round to ovoid cells, osteoclast-like multinucleated giant cells, and areas of 'smudgy' basophilic calcifications. Chromogenic in-situ hybridization showed fibroblast growth factor FGF-23 expression by the sinonasal tumour. By using immunohistochemistry, we also demonstrated, for the first time, FGF receptor 1 (FGFR1) protein overexpression in this tumour, for which FN1-FGFR1 gene fusion was not detected by fluorescence in-situ hybridization. CONCLUSIONS: Our findings indicate that up-regulation of FGFR1 in phosphaturic mesenchymal tumours can occur via mechanisms other than FN1-FGFR1 fusion, raising the possibility of FGFR1 overexpression being a potential common pathway with pathophysiological and therapeutic implications.