Molecular correlates and rate of lymph node metastasis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features and invasive follicular variant papillary thyroid carcinoma: the impact of rigid criteria to distinguish non-invasive follicular thyroid neoplasm with papillary-like nuclear features

Abstract

Thyroid tumors formerly classified as non-invasive encapsulated follicular variant of papillary thyroid carcinoma were recently renamed 'non-invasive follicular thyroid neoplasm with papillary-like nuclear features'. The current study investigated the frequency of lymph node metastasis and mutational profile of encapsulated follicular variant in the setting of a clinical practice where central neck dissection was the standard of practice. We defined the impact of rigid diagnostic criteria by regrouping such tumors based on the complete absence of papillae or presence of ≤1% papillae. Of a total of 6,269 papillary thyroid carcinomas, 152 tumors fulfilled the criteria for encapsulated follicular variant. The results were stratified according to two different diagnostic cutoff criteria with respect to the extent of papillae. When the cutoff of 1% papillae was used, the rates of lymph node metastasis and BRAF mutation were 3% and 10% in non-invasive tumors and 9% and 4% in invasive tumors, respectively. Despite the lack of invasive growth, one patient with BRAF mutant-tumor displaying predominant follicular growth and subtle papillae developed a bone metastasis. When absence of papillary structure was applied as rigid diagnostic criteria, no BRAF mutation was found in all tumors. However, central lymph node micrometastasis still occurred in 3% of non-invasive tumors. Non-V600E BRAF and RAS mutations were detected in 4% and 47% of non-invasive tumors, respectively. Our findings suggest that non-invasive follicular thyroid neoplasm with papillary-like nuclear features should not be regarded as a benign thyroid neoplasm as it can present with lymph node micrometastasis and should not be diagnosed in the presence of even a single papillary structure. Our findings underscore the original American Thyroid Association recommendation that defined non-invasive encapsulated follicular variants as low risk thyroid cancers. Clinical surveillance similar to low risk differentiated thyroid cancers and capture of this diagnostic category by Cancer Registries should be considered.

Diagnostic value of HBME‐1, CK19, Galectin 3, and CD56 in the subtypes of follicular variant of papillary thyroid carcinoma

“…Adequate nuclear features of PTC were defined as two or three of the following nuclear features: (i) alteration in size and shape (nuclear enlargement/overlapping/crowding/elongation); (ii) nuclear membrane irregularities (irregular contours, grooves, pseudoinclusions); and (iii) chromatin features of PTC (clearing with margination/glassy nuclei). FVPTCs are subdivided into IFVPTC and EFVPTC, and EFVPTCs are further subdivided into invasive EFVPTC and NIFTP according to the diagnostic criteria described in previous studies . FVPTCs with invasive tongues of tumor infiltrating adjacent non‐tumor parenchyma or diffuse growth patterns were subtyped as IFVPTC.…”

Heterogeneity of Thyroid Cancer

“…However, some papers reported NIFTPs with the BRAF V600E mutation [69] or a coexistence of TERT promoter and RAS mutations [70]. Simultaneously, another paper emphasised the importance of tightening the classification criteria, since the BRAF V600E mutation has not been present in NIFTP cases, in which papillary structures were absent [69]. As demonstrated, NIFTPs may present indolent histopathological features, which do not correspond to the molecular profile rather observed in aggressive tumours.…”

“…Current data indicate the presence of mainly RAS mutations, along with PPARγ and THADA fusions [68]. However, some papers reported NIFTPs with the BRAF V600E mutation [69] or a coexistence of TERT promoter and RAS mutations [70]. Simultaneously, another paper emphasised the importance of tightening the classification criteria, since the BRAF V600E mutation has not been present in NIFTP cases, in which papillary structures were absent [69].…”

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Can Cytology Face the Challenge of Diagnosis in the Light of the New Classification?

“…A value of 1 is assigned to each parameter, and NIFTP diagnosis requires a minimum score of 2 [7]. Cho et al [8] studied the rate of lymph node metastasis of NIFTP and concluded that it should not be diagnosed in the presence of even a single papillary structure, as stated by other authors. None of our IFV-PTC or NIFTP cases showed true papillae after careful examination.…”

“…Lesions are, therefore, divided into several categories: category I (nondiagnostic or unsatisfactory), II (benign), III (atypia of undetermined significance or follicular lesion of undetermined significance), IV (follicular neoplasm or suspicious for a follicular neoplasm), V (suspicious for malignancy), and VI (malignant). Baloch et al [13] stated that there will be an increase in the number of false-positive cases diagnosed preoperatively by FNAC. However, they also clarified that it will only affect malignant cases or those suspicious for malignancy (Bethesda categories V–VI), and most NIFTP cases supposedly classified as indeterminate (Bethesda categories III–IV).…”