Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study

Abstract

Summary Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.

Ninety-four cases of encapsulated follicular variant of papillary thyroid carcinoma: A name change to Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features would help prevent overtreatment

“…The encapsulated/well-circumscribed form may occasionally display invasion (as in this series), showing a genotype that resembles follicular adenoma and/or follicular carcinoma (RAS mutations); while the infiltrative form lacks circumscription, shows a total or partial lack of a capsule, characterized by neoplastic follicles infiltrating between non-neoplastic ones, more frequently showing BRAF mutations, and showing a greater metastatic potential and higher risk of recurrence, similar to classical papillary thyroid carcinoma. 2,[13][14][15] Encapsulated follicular variant of papillary thyroid carcinoma affects a similar age group as classical papillary carcinoma, with a 45.6 year mean in this cohort versus a 44.0 year mean in compiled literature (Table 4). Patients o 45 years have a more favorable prognosis.…”

“…Specific variants of papillary carcinoma are well recognized: well differentiated (classical, encapsulated, follicular, cystic, and microscopic), intermediate differentiated (tall cell, columnar cell, diffuse sclerosing, oncocytic, and insular), and poorly differentiated (presence of tumor necrosis and increased mitoses 1,2 ), which correlate with 'biologically indolent' and 'biologically aggressive' types. 3 There are two forms of follicular variant: the encapsulated/well circumscribed and the infiltrative form.…”

New Concept of the Encapsulated Follicular Variant of Papillary Thyroid Carcinoma and Its Impact on the Bethesda System for Reporting Thyroid Cytopathology: A Single-Institute Experience

“…Although distant metastases have been reported, now it has been accepted as an indolent entity with a restricted metastatic capacity. In essence, studies that focused on clinical outcome also supported the biologic continuum theory with increasing lymph node metastases in EFV-PTC, FV-PTC, and classical PTC, respectively [26,30,31]. …”

Papillary Thyroid Carcinoma Variants

“…An exception is the diffuse or multinodular follicular variant, which has a more aggressive clinical course [2]. The prognosis of follicular variant of PTC also depends on whether they are completely encapsulated or invasive [2,7].…”