The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct BRAF-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was initiated and promoted by pathologists. Recent Asian studies added new knowledge to the existing literature to aid a better understanding of NIFTP. Our original data and the results of a meta-analysis suggest that the initial rate of NIFTP has been overestimated, averaging 9.1% (95% confidence interval [CI] 6.0–12.7%) of all papillary thyroid cancers worldwide. The incidence of NIFTP in the Asian population (1.6%, 95% CI 0.9–2.5%; 7 studies) is significantly lower than that reported in the non-Asian series (13.3%, 95% CI 9.0–18.3%; 18 studies). Such difference could be attributed to various perceptions of histological diagnostic thresholds, different nature of papillary thyroid carcinoma, and different approaches in the management of thyroid nodules. The active surveillance for indeterminate nodules and NIFTP, largely represented in the indeterminate cytologic categories, promoted by Japanese institutions establishes a new paradigm to reduce overtreatment of these patients. The lower prevalence of NIFTP in the Asian series indicates a low impact on the risk of malignancy in cytopathology, as it was demonstrated in our original multi-institutional cohort of thyroid nodules, and may predict a low impact on the performance of commercial molecular tests. Several Korean studies addressed the issue of BRAF mutation in NIFTP, which prompted the current refinement of the diagnostic criteria for NIFTP. Our survey of Asian pathologists found that the term NIFTP has not been universally adopted in the local practice. Endocrine pathologists must promote the new entity through provision of educational activities.