How Many Papillae in Conventional Papillary Carcinoma? A Clinical Evidence-Based Pathology Study of 235 Unifocal Encapsulated Papillary Thyroid Carcinomas, with Emphasis on the Diagnosis of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features

Background: The percentage of papillae is a crucial criterion in differentiating noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from papillary thyroid carcinomas (PTCs) and in subclassifying PTC into classic and follicular variant. Since the description of NIFTP, three studies have shown that the presence of any papillae may be associated with nodal metastasis, which led to modification of the NIFTP criterion from <1% papillae to no true papillae allowed. We aim at providing clinical evidence-based data on the impact that papillary growth has on nodal spread and tumor genotype in tumors previously diagnosed as encapsulated unifocal PTC. Methods: A meticulous histopathologic examination was performed on 235 cases previously diagnosed as unifocal encapsulated PTC (U-EPTC). One hundred of these cases were subjected to BRAF V600E and NRAS Q61R immunohistochemistry. Results: In our cohort, 27 patients (12%) had lymph node metastasis (N1) at the time of initial resection. Overall, 89% of the tumors in the N1 group contained ≥50% papillae, compared with 13% in the N0/Nx group. Nodal metastases were only present in tumors with ≥1% papillae. In noninvasive U-EPTC ( n  = 161), N1 disease was seen only in tumors with ≥10% papillae. A higher percentage of papillae within the tumor also correlated with an increased frequency of BRAF V600E and decreased rate of NRAS Q61R . None of the 26 NRAS-positive cases had nodal disease, including the invasive tumors. Among 216 patients with follow-up (median: 5.2 years), 3 patients (1.5%) had distant metastases, all detected at the initial presentation. All three tumors displayed 100% follicular growth, and capsular or vascular invasion. There was no locoregional recurrence in the entire cohort. Conclusion: In U-EPTC, there is a strong correlation between high percentage of papillary growth, presence of nodal metastasis, and BRAF+/RAS- genotype regardless of invasive status. Nodal metastases were not seen in tumors with <1% papillae irrespective of invasive status. These findings indicate that the initial criterion of <1% papillae is still valid for the diagnosis of NIFTP. Reinstituting this criterion will spare a carcinoma diagnosis and unnecessary therapy with its side effects on patients who have negligible clinical risk.