LY 2157299 Disclosure br Acknowledgements Work by PV and

Disclosure
Acknowledgements Work by PV and ML is supported by the Intramural Research Program, NIDDK, NIH (DK053212-11).
Since the time when, the endocrine pathology society meeting, held at the 2015 USCAP in Boston, suggested the change in the terminology for encapsulated/non-invasive (NI-FVPCs) and renamed them as “non-invasive follicular thyroid neoplasm” with papillary like nuclear features (NIFTP), several papers have been debating the controversial nature of them (). This is also supported by the fact that NI-FVPCs, recently termed as NIFTPs, and invasive FVPT (I-FVPC), also known as encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), are not prognostically and molecularly alike () as clearly assessed by several scientific reports demonstrating that I-FVPCs show more frequent lymph nodes metastases, recurrences and prevalence of mutations whilst NI-FVPCs (accounting for 50%–70% of the entire subset of FVPCs) show a more favorable outcome (). According to the paper by Nikiforov et al., this new entity was defined by an encapsulated nodule with a follicular architecture and a set of morphological features of PTC (including nuclear membrane irregularities, ground glass appearance of the nuclei, larger nuclear size) (). Given that, in these last months, several authors aim at the evaluation of additional histopathological features which may lead to a diagnosis of NIFTPs. Thus, ancillary techniques, including immunohistochemistry (IHC) and molecular markers are likely to assess the aggressive behavior and drive to the most appropriate clinical and/or surgical management. The recent prognostic role of programmed cell death ligand (PD-L1) expression on tumor LY 2157299 was also correlated with a poor prognosis in thyroid cancers (). Specifically it has been highlighted that a high expression of PD-L1 in tumors is associated with tumor growth and metastatic behavior (). In this issue of the , Fu et al. evaluate their institutional experience with the expression of PD-L1 in EFVPTC and NIFTPs (). They provided a classification of a retrospective cohort of 174 surgically resected thyroid nodules, from 2010 to 2015, including 40 benign lesions, 52 NIFTPs, 45 EFVPTCs and 37 LT cases of FVPTC with coexisting lymphocytic thyroiditis. According to other recent papers, these authors found that cytoplasmic PD-L1 levels were significantly lower in NIFTPs as compared to EFVPTCs (<0.001). Additionally cytoplasmic PD-L1 expression in NIFTPs was similar to the benign subgroup (=0.554). The increasing levels of PD-L1 in EFVPTC can play a significant role especially in the definition of the capsular invasion (<0.001). Not only the authors find higher levels in stage II or III EFVPTC but also a significant increase in patients with stage IV in correlation with high risk of aggressive disease, distant metastases or death. Another valuable data was offered by the evidence of as high expression of PD-L1 in cases with coexisting lymphocytic infiltration as it was found in the LT subgroup of FVPTC. Nonetheless, this yield emphasizes that a higher expression of PD-L1 should be interpreted with caution as long as it can be also associated with benign entities including chronic lymphocytic thyroiditis or Hashimoto\'s thyroiditis. Importantly, Fu et al. did not find significant differences in cytoplasm PD-L1 expression between benign and NIFTPs supporting the suggestions that NIFTPs have been correctly defined as non-malignant neoplasms (). This data could also have a significant impact on the cytological evaluation of thyroid nodules in the differential diagnosis of NIFTPs versus EFVPTCs. In fact this is in agreement with the data from Maletta et al. and Bizzarro et al., who concluded that the majority of these NIFTPs are diagnosed as indeterminate lesions () on cytological samples. In this way, the data provided by Fu et al. on PD-L1 as useful marker in the discrimination between EFVPTC and NIFTP on histology could be also helpful on cytology, with important implications in clinical and surgical assessment and in lowering of the possible overtreatment.