[Tumors of the thyroid gland. Proposal for the management and study of samples from patients with thyroid neoplasms]. / Tumores de la glándula tiroides. Propuesta para el manejo y estudio de las muestras de pacientes con neoplasias tiroideas.

The recent changes in the classification and staging of thyroid tumors have arisen from the need to provide an adequate response to the exponential increase of thyroid cancer, which, however, has not been accompanied by an increase in mortality. These changes pretend to reduce overdiagnoses of malignancy, unnecessary treatment, side effects as well as cost for the health system. To this end, this article reviews recommendations for the management of thyroid surgical pathology samples with emphasis on the new terminology of the WHO classification. The basic criteria for the diagnosis of malignancy in well-differentiated thyroid carcinomas are reviewed and the criteria for NIFTP (non-invasive follicular tumor with papillary-like nuclear features) diagnosis are updated. Recommendations for the elaboration of the pathological report are also included.

Preoperative Diagnostic Categories of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in Thyroid Core Needle Biopsy and Its Impact on Risk of Malignancy.

This study was designed to evaluate the preoperative diagnostic categories of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) using thyroid core needle biopsy (CNB) and to analyze its impact on the risk of malignancy (ROM). A total of 2687 consecutive thyroid CNBs were reviewed retrospectively and classified into six diagnostic categories using a standardized reporting system similar to the Bethesda System for Reporting Thyroid Cytopathology. Diagnostic categories of CNBs were compared with the final surgical diagnoses, and the ROM in each category was calculated both before and after excluding NIFTP from malignancy. Of 946 surgically resected cases, 683 were diagnosed as papillary thyroid carcinoma (PTC), and 32 (4.7% of PTC) were reclassified as NIFTP. The CNB diagnostic categories of NIFTP were as follows: follicular neoplasm in 20 (62.5%; 14, with nuclear atypia), indeterminate lesion in 11 (34.4%), and suspicious for malignancy in one (3.1%). When combined, NIFTP and encapsulated follicular variant of PTC (EFVPTC) were more often categorized as follicular neoplasm compared with other PTC variants including infiltrative FVPTC. Exclusion of NIFTP from malignant diagnosis led to a significant decrease in the ROM in follicular neoplasm with nuclear atypia category. Thus, thyroid CNB enables to differentiate NIFTP/EFVPTC from other PTCs, providing a useful guide for optimal treatment in patients with these tumors.

Risk of Malignancy According to the Sub-classification of Atypia of Undetermined Significance and Suspicious Follicular Neoplasm Categories in Thyroid Core Needle Biopsies.

The objective of this study was to evaluate the risk of malignancy (ROM) associated with atypia of undetermined significance (AUS) and suspicious follicular neoplasm (SFN) core needle biopsy (CNB) categories after further sub-classification. Data from 2267 thyroid nodules evaluated by ultrasound-guided CNB, from January to December 2015, were retrospectively reviewed. AUS nodules (n = 556) were sub-classified as follows: (1) architectural atypia (AUS-A; n = 369, 66.4%), (2) cytologic atypia (AUS-C; n = 35, 6.3%), (3) cytologic/architectural atypia (AUS-C/A; n = 85, 15.3%), or (4) oncocytic atypia (AUS-O; n = 67, 12.1%). SFN nodules (n = 172) were sub-classified as follows: (1) architectural atypia only (SFN-A; n = 110, 64%), (2) cytologic/architectural atypia (SFN-C/A; n = 24, 14%), or (3) oncocytic atypia (SFN-O; n = 38, 22%). Diagnostic surgery was performed in 162 (30.2%) AUS cases and 105 (61%) SFN cases. The ROM of each sub-category was evaluated. The overall ROM was 15.3-52.5% in AUS nodules and 35.5-58.1% in SFN nodules. The ROM was higher in the AUS-C (22.9-88.9%) and AUS-C/A (32.9-90.3%) groups than AUS-A (11.9-40%) and AUS-O (7.5-41.7%). In the SFN category, ROM in the SFN-C/A group was also higher than SFN-A or SFN-O (37.5-75%, 40-57.9%, and 21.1-47.1%, respectively). Our study shows that the ROM was higher in AUS or SFN sub-categories with cytologic atypia than those without cytologic atypia. Because of the heterogeneous nature of AUS and SFN categories, sub-classification may be a more effective approach for risk stratification, allowing optimal management of patients with thyroid nodules.

Distinguishing non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from classic and invasive follicular-variant papillary thyroid carcinomas based on cytologic features.

INTRODUCTION: An international panel recently recommended reclassification of non-invasive follicular variant of papillary thyroid carcinoma (PTC) to non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). NIFTPs have little or no risk of recurrence and can be treated with lobectomy alone. Preoperative distinction of NIFTP from PTC will help avoid overtreatment. MATERIALS AND METHODS: All thyroid tumors with a histologic diagnosis of PTC and preceding diagnostic cytology (n = 299) over a 5-year period were identified. Cases meeting criteria for NIFTP were reclassified as such. All NIFTP cases with available cytology (n = 6) and a similar number of randomly selected invasive follicular variant of papillary thyroid carcinoma (IFVPTC; n = 9) and classic PTC (cPTC, n = 11) were evaluated for 18 cytologic features. RESULTS: A total of 35 (12%) lesions were reclassified as NIFTP, 194 (65%) were cPTC, and 70 (23%) were IFVPTC. The NIFTPs had a preceding cytologic interpretation of benign (31%), atypia of undetermined significance (34%), follicular neoplasm (9%), suspicious for malignancy (12%), or malignant (14%). Cytologically, NIFTP was distinguished from cPTC by absence of any architectural features in all 6 cases, and by absence of pseudoinclusions (P < 0.001) and multinucleated giant cells (P = 0.027) in nearly all. Nuclear pseudoinclusions (P = 0.001), marginal micronucleoli (P = 0.018), irregular branching sheets (P = 0.025), and linear arrangement (P = 0.025) favored IFVPTC over NIFTP. CONCLUSIONS: NIFTPs were originally assigned to a variety of cytologic categories. There are several cytologic differences between NIFTP and cPTC or IFVPTC. Our findings support restricting the definitive diagnosis of PTC to cases with architectural features of PTC and/or intranuclear pseudoinclusions.

Application of Strict Criteria for Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and Encapsulated Follicular Variant Papillary Thyroid Carcinoma: a Retrospective Study of 50 Tumors Previously Diagnosed as Follicular Variant PTC.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a designation for a subset of follicular variant papillary thyroid carcinoma (FVPTC). Encapsulated FVPTC has been shown to be a fairly indolent tumor, and NIFTP are expected to represent the most indolent subset of these tumors. Many of the exclusion criteria for NIFTP related to architecture and a lack of psammoma bodies are designed to preclude the inclusion of more aggressive non-FVPTC tumors in this indolent group and also exclude the diagnosis of FVPTC. In addition to strict application of histologic features to ensure that NIFTP represents a subset of encapsulated FVPTC without invasion, other exclusion criteria including high mitotic activity and necrosis may also lead to a lack of one-to-one correlation between the diagnosis of NIFTP and encapsulated FVPTC without invasion. In this series, 50 cases previously diagnosed as FVPTC over a 2-year period from a large academic center are retrospectively reviewed for reclassification as NIFTP. Additionally, cases not meeting criteria for NIFTP are more accurately classified using the most up to date WHO criteria. Prior BRAF V600E mutation testing was examined for these tumors when available. Seventeen of 50 (34%) tumors met criteria for classification as NIFTP and, 17 (34%) were classified as encapsulated FVPTC with invasion. Strict application of architectural features led to classification of 12 (24%) tumors as non-FVPTC with a variety of more aggressive designations. Tumors classified as NIFTP and encapsulated FVPTC with invasion lacked lymph node metastases (0/4; 0/7, respectively) and BRAF mutations (0/12; 0/13, respectively). In contrast, infiltrative FVPTC, encapsulated PTC with or without invasion, and conventional PTC showed more aggressive features with lymph node metastases and BRAF V600E mutations. One case not meeting criteria for NIFTP maintained the diagnosis of encapsulated FVPTC without invasion but demonstrated significant mitotic activity (three mitoses/ten HPF) and lacked lymph node metastases and BRAF V600E mutation. These findings demonstrate the importance of using strict criteria, especially the lack of true papillary architecture, for the diagnosis of NIFTP and encapsulated FVPTC to ensure that only truly indolent tumors will be included in these diagnoses and to allow tumors with potential for more aggressive behavior to be appropriately treated.

The History of the Follicular Variant of Papillary Thyroid Carcinoma.

Context: This review provides historical context to recent developments in the classification of the follicular variant of papillary thyroid carcinoma (FVPTC). The evolution of the diagnostic criteria for papillary thyroid carcinoma is described, clarifying the role of molecular analysis and the impact on patient management. Methods: A PubMed search using the terms "follicular variant" and "papillary thyroid carcinoma" covering the years 1960 to 2016 was performed. Additional references were identified through review of the citations of the retrieved articles. Results: The encapsulated/well-demarcated, noninvasive form of FVPTC that occurs annually in 45,000 patients worldwide was thought for 30 years to be a carcinoma. Many studies have shown almost no recurrence in these noninvasive tumors, even in patients treated by surgery alone without radioactive iodine therapy. The categorization of the tumor as outright cancer has led to aggressive forms of treatment, with their side effects, financial costs, and the psychological and social impacts of a cancer diagnosis. Recently, the encapsulated/well-demarcated, noninvasive FVPTC was renamed as noninvasive follicular thyroid neoplasm with papillary-like nuclear features. The new terminology lacks the carcinoma label, enabling clinicians to avoid aggressive therapy. Conclusions: By understanding the history of FVPTC, future classification of tumors will be greatly improved.

The Ethical Implications of the Reclassification of Noninvasive Follicular Variant Papillary Thyroid Carcinoma.

BACKGROUND: Several studies have highlighted the lack of consensus in the diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC). An international multidisciplinary panel to address the controversy was assembled at the annual meeting of the Endocrine Pathology Society in March of 2015, leading to the recent publication reclassifying encapsulated (or noninvasive) FVPTC (EFVPTC) as a benign neoplasm. Does this change in histologic taxonomy warrant a change in clinical practice, and how should it affect those who have been given this diagnosis in the past? We consider the financial and psychological impact of this reclassification and discuss the ethical, legal, and practical issues involved with sharing this information with the patients who are affected. SUMMARY: The total direct and indirect cost of thyroid cancer surveillance in patients is significant. High levels of clinically relevant distress affect up to 43% of patients with papillary thyroid carcinoma, as estimated by the Distress Thermometer developed by the National Comprehensive Cancer Network for detecting distress in cancer patients. Although there are currently no legal opinions that establish a precedent for recontacting patients whose clinical status is altered by a change in nomenclature, the prudent course would be to attend to the requirements of medical ethics. CONCLUSION: Informing patients with a previous diagnosis of EFVPTC that the disease has been reclassified as benign is expected to have a dramatic effect on their surveillance needs and to alleviate the psychological impact of living with a diagnosis of cancer. It is important to re-evaluate the pathologic slides of those patients at risk to ensure that the invasive nature of the tumor is comprehensively evaluated before notifying a patient of a change in diagnosis. The availability of the entire tumor for evaluation of the capsule may prove to be a challenge for a portion of the population at risk. We believe that it is the clinician's professional duty to make a sincere and reasonable effort to convey the information to the affected patients. We also believe that the cost savings with respect to the need for additional surgery, radioactive iodine, and rigorous surveillance associated with a misinterpretation of the biology of the diagnosis of EFVPTC in less experienced hands will likely more than offset the cost incurred in histologic review and patient notification.

Does bethesda category predict aggressive features in malignant thyroid nodules?

BACKGROUND: It has been speculated that the Bethesda Classification System for thyroid fine-needle aspirate (FNA) may be used to predict aggressive features among histologically proven malignancies. We sought to evaluate whether malignancies that were characterized as Bethesda category V or VI have more aggressive features than malignancies that were category III or IV. METHODS: A prospectively maintained database was reviewed to identify thyroid malignancies treated at a single center from 2004 to 2009. Only cancers that could be definitively matched to a preoperative FNA were included. Associations between Bethesda category, patient demographics, histopathologic findings, and outcomes were examined. RESULTS: A total of 360 cancers were analyzed: 73 (20 %) were Bethesda category III or IV and 287 (80 %) were category V or VI. The majority of Bethesda III and IV cancers were follicular variants of papillary thyroid carcinoma (fvPTC), whereas the majority of Bethesda V and VI cancers were classic PTC (52 and 67 %, respectively, p < 0.01). Extrathyroidal extension (30 vs. 16 %, p = 0.02), lymph node metastases (50 vs. 31 %, p = 0.05), and multifocality (51 vs. 37 %, p = 0.03) were more common among Bethesda V and VI nodules. However, when Bethesda III or IV classic PTC and fvPTC were compared to Bethesda V or VI cancers of the same histologic subtype, there were no differences in any features. Recurrence and overall survival were the same in all groups. CONCLUSIONS: Bethesda category may help to predict the most likely histologic subtype of thyroid cancer, but it does not have any prognostic significance once the histologic diagnosis is known.

Pitfalls in the diagnosis of follicular epithelial proliferations of the thyroid.

The diagnosis of follicular epithelial neoplasms is an area of controversy. We provide our experience with common problems that practising pathologists face when confronted with follicular epithelial proliferations. One of the major issues is the recognition of the diagnostic nuclear features of papillary thyroid carcinoma and reactive cytologic atypia. We discuss the definitions of capsular invasion, vascular invasion, and extrathyroidal extension and their implications in cancer diagnosis and staging. We propose unified terminology for benign follicular epithelial proliferations in the setting of multinodular goiter. We also review challenges related to oncocytic change, malignant transformation in benign nodules, focal dedifferentiation, and the application of ancillary tools in thyroid pathology. We believe that this review contains comprehensive and up to date information that will be of value to pathologists who practice surgical pathology of thyroid.

Encapsulated papillary thyroid carcinoma, follicular variant: a misnomer.

Papillary thyroid carcinoma (PTC) has long been diagnosed based on its unique nuclear features (PTC-N); however, significant observer discrepancies have been reported in the diagnosis of encapsulated follicular patterned lesions (EnFPLs), because the threshold of PTC-N is subjective. An equivocal PTC-N may often occur in non-invasive EnFPLs and benign/malignant disagreements often create serious problems for patients' treatment. This review collects recent publications focusing on the so-called encapsulated follicular variant of papillary thyroid carcinoma (EnFVPTC) and tries to emphasize problems in the histopathological diagnosis of this spectrum of tumors, which covers encapsulated common-type PTC (EncPTC), EnFVPTC, well-differentiated tumor of uncertain malignant potential (WDT-UMP), follicular adenoma (FA) with equivocal PTC-N and minimally invasive follicular carcinoma (mFTC). We propose that EnFVPTC and other EnFPLs with equivocal PTC-N should be classified into a unified category of borderline malignancy, such as well-differentiated tumor of uncertain behavior (WDT-UB), based on their homogeneous excellent outcome. It is suggested that the unified nomenclature of these lesions may be helpful to reduce significant observer disagreements in diagnosis, because complete agreement in the diagnosis of an EncPTC, EnFVPTC or FA by all pathologists may be not possible for this problematic group of tumors. In conclusion, a malignant diagnosis of EnFVPTC should not be used to cover this spectrum of tumors until uncertainty about the nature of this lesion is settled, whether it is benign, precancerous or malignant.

What if many follicular variant papillary thyroid carcinomas are not malignant? A review of follicular variant papillary thyroid carcinoma and a proposal for a new classification.

OBJECTIVES: To review the relevant literature concerning follicular variant of papillary thyroid carcinoma (FVPTC) with an emphasis on the heterogeneity of this disorder and to propose a new classification for FVPTC on the basis of molecular diagnostics and apply the classification to a typical case. METHODS: English-language articles pertaining to FVPTC published between January 1990 and December 2010 were reviewed. RESULTS: FVPTC is particularly vexing. The criteria for diagnosing FVPTC appear to have changed over the years. Pathologists often disagree about the diagnosis of FVPTC. The clinical behavior of these tumors is variable. Molecular diagnostic studies suggest that FVPTC represents a heterogeneous group of disorders rather than a single entity. CONCLUSIONS: On the basis of the available data, it is proposed that individual cases of FVPTC be reclassified as papillary thyroid carcinoma, follicular thyroid carcinoma, or follicular adenomas, after appropriate molecular biologic studies have been completed. Long-term follow-up studies to validate this classification are necessary.

Encapsulated malignant follicular cell-derived thyroid tumors.

Encapsulated malignant follicular cell-derived thyroid tumors are subject to considerable controversies. This group includes encapsulated follicular variant of papillary carcinoma (FVPTC) and encapsulated (so-called minimally invasive) follicular carcinoma (EFC). FVPTC usually presents as an encapsulated tumor and less commonly as a partially/nonencapsulated infiltrative neoplasm. The encapsulated form rarely metastasizes to lymph node, whereas infiltrative tumors often harbor nodal metastases. Encapsulated FVPTC have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF > RAS mutations). Noninvasive encapsulated FVPTC are extremely indolent even if treated with lobectomy without radioactive iodine therapy. Although most EFC are thought to have an excellent outcome, there are cases of EFC that recur and metastasize. EFC with angioinvasion, especially if extensive, have a significant rate of distant recurrence. Encapsulated FVPTC have a molecular profile and a clinical behavior very similar to the follicular adenoma/carcinoma class of tumor. If noninvasive, encapsulated FVPTC should be treated in a very conservative fashion. EFC with angioinvasion, especially if extensive, should not be termed minimally invasive in order to prevent undertreatment of the patient.

Familial follicular cell tumors: classification and morphological characteristics.

Familial follicular cell-derived well-differentiated thyroid cancer, papillary (PTC), and follicular thyroid carcinomas (FTC), accounts for 95% of thyroid malignancies. The majority of are sporadic, and at least 5% of these patients will have familial disease. Familial thyroid syndromes are classified into familial medullary thyroid carcinoma (FMTC), derived from calcitonin-producing C cells, and familial follicular cell tumors or non-medullary thyroid carcinoma (FNMTC), derived from follicular cells. Twenty-five percent of patients with medullary thyroid cancer (MTC) have a familial form; however, this accounts for only 1% of all patients with thyroid cancer. The familial follicular cell-derived lesions or familial non-medullary thyroid cancer can be divided into two clinical-pathological groups. The first group includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN-hamartoma tumor syndrome (Cowden disease; PHTS), Carney complex, Werner syndrome, and Pendred syndrome. The second group includes familial syndromes characterized by predominance of papillary thyroid carcinoma (PTC), such as pure fPTC, fPTC associated with papillary renal cell carcinoma, and fPTC with multinodular goiter. Most of the progress in the genetics of familial thyroid cancer has been in patients with MTC. This is usually a component of multiple endocrine neoplasias IIA or IIB, or as pure familial medullary thyroid carcinoma syndrome. The genetic events in the familial C-cell-derived tumors are known and genotype-phenotype correlations are well established. The mutations in patients with isolated NMFTC have not been as well defined as in MTC. In many cases, patients have a known familial syndrome that has defined risk for thyroid cancer. The clinician must be knowledgeable in recognizing the possibility of an underlying familial syndrome when a patient presents with thyroid cancer. Some characteristic thyroid morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetics evaluation.

Follicular variant of papillary thyroid carcinoma: a clinicopathologic study of a problematic entity.

BACKGROUND: There is continuous debate regarding the optimal classification, prognosis, and treatment of the follicular variant of papillary thyroid carcinoma (FVPTC). The objective of this study was 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. METHODS: All patients with FVPTC, follicular thyroid adenoma (FTA), and follicular thyroid carcinoma (FTC) who were diagnosed between 1980 and 1995 were reviewed and reclassified according to the currently accepted definition of FVPTC. The tumors were separated into encapsulated and nonencapsulated (infiltrative/diffuse) types. Encapsulated tumors were subdivided further into tumors with or without capsular/vascular invasion. These different subtypes of FVPTC were correlated with outcome and with other clinicopathologic parameters. RESULTS: After review by 4 pathologists, 78 patients were included in the study. Sixty-one of 78 patients (78%) had encapsulated tumors (18 invasive, 43 noninvasive), and 17 patients had nonencapsulated tumors (infiltrative/diffuse). The gender distribution, age at presentation, and tumor size did not differ between patients with encapsulated and nonencapsulated FVPTC. Patients who had encapsulated FVPTC had a significantly lower rate of marked intratumor fibrosis (18%), extrathyroid extension (5%), and positive margins (2%) compared with patients who had nonencapsulated tumors (88%, 65%, and 50% respectively; P < .0001). Regional lymph node metastases were present in 14 of 78 patients (18%), and no patients had distant metastases. The lymph node metastatic rate was significantly higher in patients who had nonencapsulated tumors (11 of 17 patients; 65%) compared with patients who had encapsulated neoplasms (3 of 61 patients; 5%; P < .0001). In addition, lymph node metastases were not detected in any noninvasive, encapsulated FVPTCs. With a median follow-up of 10.8 years, only 1 patient developed a recurrence, which occurred in an encapsulated FVPTC that had numerous invasive foci. None of the patients with noninvasive, encapsulated FVPTCs developed recurrences, including 31 patients who underwent lobectomy alone, with a median follow-up of 11.1 years. CONCLUSIONS: FVPTC appeared to be a heterogeneous disease composed of 2 distinct groups: an infiltrative/diffuse (nonencapsulated) subvariant, which resembles classic papillary carcinoma in its metastatic lymph node pattern and invasive growth, and an encapsulated form, which behaves more like FTA/FTC. Patients who had noninvasive, encapsulated FVPTCs did not develop lymph node metastases or recurrences and could be treated by lobectomy alone. If the current findings are confirmed, then strong consideration should be given to reclassifying encapsulated FVPTC as an entity that is close to the FTA/FTC class of tumors.

Follicular variant of papillary thyroid carcinoma: clinical-pathological characterization and long-term follow-up.

PURPOSE: Questions arise concerning the behavior and prognosis of the follicular variant of papillary thyroid carcinoma. PATIENTS AND METHODS: Between 1990 and 2003, 92 patients with follicular variant of papillary carcinoma (group A) were enrolled in a long-term study and compared with control groups of follicular thyroid carcinoma (group B, 40 cases) and pure papillary thyroid carcinoma (group C, 99 subjects). RESULTS: Gender (female/male), age, and follow-up duration (years, mean+/-standard error) in groups B, A, and C were 36/4, 43+/-3, 11+/-1.1; 79/13, 46+/-2, 9.5+/-0.7; and 82/17, 44+/-1, 10+/-0.6, respectively. At the time of diagnosis, the rates of extensive extra thyroidal local spread, bilateral lesions, and vascular invasion were higher in group A than in group C. The rate of metastasis tumors was higher in group A than in group C and was comparable in groups A and B. Complete remission was reported in 95% of group B patients, 98% of group C individuals, and in only 77% of group A subjects. Persistent stable lesions and progressive disease rates in groups B, A, and C were 2.5% and 2.5%, 15% and 8%, and 0% and 2%, respectively. The survival rates at the end of the study were 100% in all cohorts, but the cumulative dose of administered radioiodine in group A was higher than in group C and was comparable to that given in group B. Metastases dedifferentiation was observed only in the group A (three patients). DISCUSSION: Follicular variant of papillary thyroid carcinoma may be more aggressive than previously considered and should be clearly distinguished from the two other forms of well-differentiated thyroid carcinoma.