Endocr Pathol DOI 10.1007/s12022-015-9376-5
Encapsulated Thyroid Carcinoma of Follicular Cell Origin Bin Xu 1 & Ronald Ghossein 1
# Springer Science+Business Media New York 2015
Abstract Encapsulated carcinomas of follicular cell origin are subject to considerable controversies. This group includes an encapsulated/well-circumscribed (E/WC) follicular variant of papillary carcinoma (FVPTC) and encapsulated follicular and Hurthle cell carcinoma (EFC, EHC respectively). FVPTC usually presents as an E/WC tumor and less commonly as an infiltrative neoplasm. E/WC FVPTC rarely metastasizes to lymph nodes, whereas infiltrative tumors often present with cervical nodal metastases. Many studies revealed FVPTC in general to be genetically close to the follicular adenomas (FA)/ EFC group of tumors. This is particularly true for the E/WC FVPTC which has a high rate of RAS and lack BRAFV600E mutations. Infiltrative FVPTC has an opposite molecular profile closer to classical papillary carcinoma than to FA/EFC (BRAFV600E>RAS mutations). Noninvasive E/WC FVPT Cs are extremely indolent even if treated with lobectomy alone. While EFC and EHC with capsular invasion only have an excellent outcome, those with extensive (≥4 foci) lymphovascular invasion (LVI) have a significant rate of distant recurrence. The prognosis of those with focal LVI seems good, but more studies are needed to confirm their behavior. In EHC, those with extensive/significant LVI have a different RNA expression profile than those with less LVI. EHC appear to recur earlier, are less RAI avid, and have a different mutation profile than EFC. Noninvasive E/WC FVPTC should be treated conservatively. There is therefore a need to reclassify the E/WC FVPTC in order to prevent overtreatment. In view
* Ronald Ghossein
[email protected] 1
Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
of their molecular and behavioral differences, EHC should not be considered a subset of EFC. Keywords Encapsulated thyroid carcinoma of follicular cell origin . Papillary thyroid carcinoma . Follicular carcinoma . Hurthle cell carcinoma
Introduction There are many problems and controversies in the classification of thyroid carcinomas of follicular cell origin. These controversies have a significant impact on the management of patients with thyroid carcinomas, often leading to overtreatment. The most diagnostically and prognostically challenging class of carcinomas is encapsulated carcinoma of follicular cell origin. This group of carcinomas includes frequently encountered tumors such as the follicular variant of papillary thyroid carcinomas (FVPTCs), the less common encapsulated follicular and Hurthle cell carcinomas (HCCs), as well as very rare neoplasms such as encapsulated poorly differentiated and anaplastic carcinomas. This article will focus on the two most common and problematic groups of tumors: the follicular variant of papillary thyroid carcinoma and encapsulated follicular and Hurthle cell carcinoma. Follicular Variant of Papillary Thyroid Carcinoma The prevalence of FVPTC among patients with papillary thyroid carcinoma (PTC) is variable ranging from 9 to 25 % [1–5]. This variation is most probably related to a difference in diagnostic criteria among authors. Most recently, we have seen a significant increase in the diagnosis of this entity. In one institution, PTC growing as FVPTC (of all tumor sizes) rose from 25 % of all PTC in the late 1970s and early 1980s to
Endocr Pathol
56 % of all PTC in 2009, becoming the most common form of PTC [5]. This variant is composed entirely or almost completely of follicles, which are lined by cells having the nuclear features of papillary carcinoma [6]. Thus, FVPTC shares with follicular adenoma (FTA) and carcinoma (FTC) the presence of follicles. When FVPTC is nonencapsulated and infiltrates the surrounding thyroid parenchyma, the diagnosis of carcinoma usually poses no diagnostic challenge. For the encapsulated/well-circumscribed tumor without invasion of surrounding thyroid tissue, the diagnosis of malignancy relies solely on the presence of the nuclear features of PTC (e.g., nuclear clearing, overlapping, and grooves) which often can be borderline. Psammoma bodies which are considered a hallmark of PTC are very rare in these tumors, as are nuclear pseudo-inclusions, rendering the diagnosis of carcinoma even more difficult. Therefore, the diagnosis of noninvasive, encapsulated/well-circumscribed FVPTC versus follicular adenoma is prone to considerable inter- and intra-observer variability [7–9]. This diagnostic dilemma has very important therapeutic implications. For many years and even nowadays, many physicians in the USA will recommend completion thyroidectomy followed by radioactive iodine therapy (RAI) if a FVPTC is greater than 1–1.5 cm in size [10]. Even the most recent 2009 American Thyroid Association guidelines, which is considered conservative when it comes to treatment, recommend for noninvasive FVPTC a therapy similar to the one designed for garden-variety intrathyroidal PTC of similar size [11]. For example, based on the American Thyroid Association guidelines, a 4.1-cm FA is treated with lobectomy alone while a similar size noninvasive EFVPTC is subjected to total thyroidectomy and RAI remnant ablation. In the early 1990s, some authors have suggested that patients with encapsulated, noninvasive FVPTC have an excellent prognosis and, thus, believed that only a lobectomy is needed [6]. However, at that time, there were no outcome data with long median follow-up from a large cohort of patients with FVPTC. In 2000, Baloch and LiVolsi reported on 5 encapsulated FVPTCs which metastasized to distant sites in the absence of lymph node metastases, mimicking the behavior of FTC [12]. Other authors reported that FVPTC has a significantly lower metastatic lymph node rate and is more often encapsulated than classic PTC [13, 14]. Several groups have attempted to analyze FVPTC at the molecular and chromosomal levels [13, 15, 16]. All of those studies concurred that the molecular profile of the FVPTC seems to be closer to that of the FTA/FTC group than to classic PTC, supporting further consideration of the classification of FVPTC. The ultimate proof that the molecular profile of FVPTC in general is different from classical PTC and close to the FA/FTC group of tumor came from The Cancer Genome Atlas (TCGA) analysis of 496 PTC [17]. Using various genotyping platforms (e.g., mRNA, microRNA, and
methylation), FVPTC was shown to be mostly RAS driven and distinctly different than classical and tall cell variant PTC. The hint coming from the molecular literature prompted us in 2006 to assess the behavior of FVPTC (especially its encapsulated form) and shed more light on its true position in the classification scheme of well-differentiated thyroid carcinoma. For that purpose, we undertook a clinicopathologic study of all patients with FVPTC who were seen at Memorial Sloan Kettering Cancer Center between 1980 and 1995 [18]. To understand the biologic behavior of FVPTC, we excluded all subcentimeter FVPTCs and allowed only 2 additional foci of papillary microcarcinoma as additional malignancy. FVPTC tumors were classified according to histologic growth patterns as encapsulated versus infiltrative neoplasms. The encapsulated subset was subdivided further according to the presence or absence of invasion in a manner similar to that used to differentiate FTA from FTC. The encapsulated FVPT Cs outnumbered their infiltrative counterparts (only 17 tumors were infiltrative vs. 61 encapsulated FVPTCs). In our study, patients who had infiltrative FVPTC had a significantly greater frequency (P
