Follicular Cell-derived Tumors Research Articles

Oncocytic Follicular Cell-Derived Thyroid Tumors With Papillary Growth Pattern: A Clinicopathologic Study of 32 Cases.

Oncocytic thyroid tumors displaying a papillary growth pattern are rare and may cause diagnostic problems. To examine the clinicopathologic features of a series of 32 follicular cell-derived tumors composed of cells with oncocytic cytoplasm and displaying papillary architecture. Thirty-two cases were collected and studied to assess clinicopathologic features, including immunohistochemical and molecular testing for BRAF V600E. The patients were 26 women and 6 men, aged 17 to 77 years. The nodules ranged from 0.3 to 6.0 cm. Eighteen cases showed features of oncocytic hyperplastic nodules and were identified against a background of thyroid follicular nodular disease; 4 cases showed features of oncocytic follicular adenoma; and 10 cases corresponded to carcinomas with oncocytic and papillary features. Nuclear features of papillary thyroid carcinoma were absent or exceedingly rare. All cases were negative for HBME-1 and cytokeratin 19 (CK19) and wild type for BRAF V600E. Follow-up in 25 patients showed that all patients with hyperplastic nodules and oncocytic follicular adenomas were alive and well and free of disease from 7 to 20 years. One patient with oncocytic follicular carcinoma showed metastases and died of tumor at 16 months; 2 patients with carcinoma had metastases and recurrence at 6 and 7 years; and 5 patients with invasive tumors were free of disease from 5 to 10 years. Oncocytic thyroid tumors with papillary features can span a spectrum from benign hyperplastic, to encapsulated neoplastic, to invasive malignant lesions. Owing to their papillary features, it is important not to confuse them for other types of thyroid tumors, such as oncocytic papillary thyroid carcinoma.

Genomic and transcriptomic analyses of thyroid cancers identify DICER1 somatic mutations in adult follicular-patterned RAS-like tumors.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Several genomic and transcriptomic studies explored the molecular landscape of follicular cell-derived TCs, and BRAFV600E, RAS mutations, and gene fusions are well-established drivers. DICER1 mutations were described in specific sets of TC patients but represent a rare event in adult TC patients. Here, we report the molecular characterization of 30 retrospective follicular cell-derived thyroid tumors, comprising PTCs (90%) and poorly differentiated TCs (10%), collected at our Institute. We performed DNA whole-exome sequencing using patient-matched control for somatic mutation calling, and targeted RNA-seq for gene fusion detection. Transcriptional profiles established in the same cohort by microarray were investigated using three signaling-related gene signatures derived from The Cancer Genome Atlas (TCGA). The occurrence of BRAFV600E (44%), RAS mutations (13%), and gene fusions (13%) was confirmed in our cohort. In addition, in two patients lacking known drivers, mutations of the DICER1 gene (p.D1709N and p.D1810V) were identified. DICER1 mutations occur in two adult patients with follicular-pattern lesions, and in one of them a second concurrent DICER1 mutation (p.R459*) is also observed. Additional putative drivers include ROS1 gene (p.P2130A mutation), identified in a patient with a rare solid-trabecular subtype of PTC. Transcriptomics indicates that DICER1 tumors are RAS-like, whereas the ROS1-mutated tumor displays a borderline RAS-/BRAF-like subtype. We also provide an overview of DICER1 and ROS1 mutations in thyroid lesions by investigating the COSMIC database. Even though small, our series recapitulates the genetic background of PTC. Furthermore, we identified DICER1 mutations, one of which is previously unreported in thyroid lesions. For these less common alterations and for patients with unknown drivers, we provide signaling information applying TCGA-derived classification.

DICER1 Mutations Do Not Always Indicate Dismal Prognosis in Pediatric Poorly Differentiated Thyroid Carcinomas.

Progress in the field of pediatric thyroid pathology has linked DICER1 mutations to benign follicular cell-derived thyroid tumors (e.g., follicular adenoma with papillary architecture, follicular nodular disease), low-risk follicular cell-derived differentiated thyroid carcinomas and PDTCs enriched in fatal or recurrent/progressive disease. The dismal outcome of DICER1-harboring pediatric PDTCs stems from a limited number of reported patients' data given the rarity of pediatric PDTCs. In light of the former observations, the current study assessed clinicopathological variables of a series of 5 pediatric (≤ 18 years old) PDTCs using the Turin criteria (WHO 2022) and also examined the status of DICER1 and TERT promoter mutations. Five PDTCs (3 males, 2 females) were included in the study. The mean age at the time of diagnosis was 15.4 years. No patients had a history of DICER1 syndrome-related tumors or other clinicopathological diagnostic features of DICER1 syndrome. The mean tumor size was 3.9 cm. All tumors were completely submitted for microscopic examination. There was increased mitotic activity ranging from 3 to 10 mitoses per 2 mm2. Tumor necrosis was present in two cases. No PDTC harbored TERT promoter mutation. DICER1 hot spot mutation was identified in one (20%) tumor. The DICER1-mutant tumor had neither associated differentiated thyroid carcinoma component nor other pathological findings in the adjacent thyroid parenchyma. The DICER1-mutant PDTC showed widely invasive growth confined to the thyroid parenchyma. Despite the widely invasive growth, the tumor lacked vascular invasion. Two DICER1 wild-type PDTCs had lymphocytic thyroiditis and another one had underlying follicular nodular disease and/or follicular adenomas. Three DICER1 wild-type PDTCs also had an associated differentiated thyroid carcinoma component with no high-grade features. No abnormal p53 expression (overexpression or global loss) was recorded in all tested tumors. Four patients had follow-up data with a mean follow-up time of 60.25 months (range: 18-86 months). One patient with no evidence of disease recurrence died of anunrelated cause after 18 months of the initial surgery, all remaining patients were alive with no distant metastasis at their last visit. Of the 4 patients with lymph node (LN) dissection, one DICER1 wild-type PDTC had recurrent nodal disease. During the follow-up period (72 months), no local recurrence or distant metastases was detected in the DICER1-mutant PDTC. Taken together all reported findings from earlier series, DICER1 mutations alone may not necessarily indicate dismal outcome in a subset of pediatric PDTCs. The occurrence of additional genomic alterations as discussed in some earlier reports may be contributing to tumor progression or aggressivity of pediatric PDTCs. The lack of vascular invasion in the current DICER1-mutant pediatric PDTC may also explain an indolent biologic outcome. The risk escalation of DICER1 mutations should integrate the status of additional genetic events and well-established pathologic variables in order to ensure predictive dynamic risk stratification in DICER1-mutant pediatric PDTCs. Additional studiesare needed to corroborate the findings of this study and advance our knowledge in pediatric thyroid neoplasia.

A Matched-Pair Analysis of Nuclear Morphologic Features Between Core Needle Biopsy and Surgical Specimen in Thyroid Tumors Using a Deep Learning Model.

Core needle biopsy (CNB) is a method that can be used as an alternative to fine-needle aspiration for the sampling of thyroid nodules to provide a preoperative diagnosis. Nuclear atypia is of paramount importance in diagnosing thyroid tumors. We aimed to identify the differences in nuclear morphologic features between CNB and surgical specimens. Quantitative image analysis was performed on whole slide images (WSI) of paired CNB and surgical specimens from 50 follicular cell-derived tumors including adenoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and carcinoma. The nuclear features of tumor cells were extracted from WSI using a pre-trained deep-learning model. In matched-pair analysis, the ratios (surgical specimens-to-CNB) of the mean nuclear diameters and the areas of the tumor cells were 1:0.75-0.85 and 1:0.54-0.73 according to the tumor types, respectively. The ratio of the nuclear optical density of tumor cells was 1.68-2.44 times higher in CNB specimens than it was in their corresponding surgical specimens. The significant nuclear size reduction and optical density increase in CNB were most prominent in papillary carcinoma cells. Normal follicular cells showed nuclear size reduction in CNB but no change in nuclear optical density between CNB and surgical specimens. Nuclear vacuolar artifacts mimicking nuclear pseudoinclusions were frequently seen in CNB regardless of the tumor types. In conclusion, tumor cells in CNB showed marked nuclear shrinkage, darker nuclear staining, and nuclear vacuolar changes. Awareness of the morphological differences according to the sampling types can facilitate correct diagnosis in thyroid histopathology.

Pathological Analysis of Encased Resected Recurrent Nerves in Locally Invasive Thyroid Cancer.

Simple SummaryThyroid cancer encasing the recurrent nerve is rare, and the decision to resect or preserve the nerve is multifactorial. The aim of this retrospective study was to evaluate the rate of actual invasion of the nerve beyond the nerve sheath in cancers encasing the nerve. Fifty-two patients were included: 7 cases of medullary thyroid carcinoma, 8 papillary thyroid carcinomas in children and 37 follicular derived cancers in adults. Tumor-related vocal fold paralysis was present in 30% of cases. The nerve was invaded in 82% of follicular cell-derived tumors, 88% of pediatric cases, and 100% of medullary carcinomas. Only agressive histology was a risk factor for nerve invasion. Vocal fold paralysis was not predictive. To our knowledge, this is one of the largest series with pathologic analysis of resected recurrent nerves, showing a high rate of nerve invasion in these rare cases of cancer encasing the reucrrent nerve.Objective: Thyroid cancer encasing the recurrent nerve is rare, and the decision to resect or preserve the nerve is multifactorial. The objective of this study was to histopathologically analyze resected encased nerves to assess the rate of nerve invasion and risk factors. Materials and Methods: A retrospective study was carried out on consecutive patients with resection of the recurrent nerve for primary or recurrent follicular cell-derived or medullary thyroid carcinoma from 2005 to 2020. Demographics, pathology, locoregional invasion, metastases, recurrences and survival were analyzed. Slides were reviewed blindly by two specialized pathologists (AAG, RC) for diagnosis of invasion deep to the epineurium. Results: Fifty-two patients were included: 25 females; average age, 55 (range 8–87). In total, 87% percent (45/52) were follicular cell-derived with 17/45 (37.8%) aggressive variants; 13% (7/52) were medullary carcinoma. Preoperative vocal fold (VF) paralysis was present in 16/52 (30.7%). Pathologically, the nerve was invaded in 44/52 cases (85%): 82% of follicular cell-derived tumors (37/45), 88% of pediatric cases, and 100% of medullary carcinomas (7/7). Nerve invasion was observed in 11/16 (69%) with preoperative VF paralysis and 33/36 (92%) with normal VF function. Only aggressive histology was correlated with nerve invasion in follicular cell-derived tumors (p = 0.019). Conclusions: The encased nerves were pathologically invaded in 82% of follicular cell-derived tumors and in 100% of medullary carcinomas. Nerve invasion was statistically correlated with aggressive histopathological subtypes and was observed in the absence of VF paralysis in 92% of cases.

Overview of the 2022 WHO Classification of Thyroid Neoplasms.

This review summarizes the changes in the 5th edition of the WHO Classification of Endocrine and Neuroendocrine Tumors that relate to the thyroid gland. The new classification has divided thyroid tumors into several new categories that allow for a clearer understanding of the cell of origin, pathologic features (cytopathology and histopathology), molecular classification, and biological behavior. Follicular cell-derived tumors constitute the majority of thyroid neoplasms. In this new classification, they are divided into benign, low-risk, and malignant neoplasms. Benign tumors include not only follicular adenoma but also variants of adenoma that are of diagnostic and clinical significance, including the ones with papillary architecture, which are often hyperfunctional and oncocytic adenomas. For the first time, there is a detailed account of the multifocal hyperplastic/neoplastic lesions that commonly occur in the clinical setting of multinodular goiter; the term thyroid follicular nodular disease (FND) achieved consensus as the best to describe this enigmatic entity. Low-risk follicular cell-derived neoplasms include non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), thyroid tumors of uncertain malignant potential, and hyalinizing trabecular tumor. Malignant follicular cell-derived neoplasms are stratified based on molecular profiles and aggressiveness. Papillary thyroid carcinomas (PTCs), with many morphological subtypes, represent the BRAF-like malignancies, whereas invasive encapsulated follicular variant PTC and follicular thyroid carcinoma represent the RAS-like malignancies. This new classification requires detailed subtyping of papillary microcarcinomas similar to their counterparts that exceed 1.0cm and recommends not designating them as a subtype of PTC. The criteria of the tall cell subtype of PTC have been revisited. Cribriform-morular thyroid carcinoma is no longer classified as a subtype of PTC. The term "Hürthle cell" is discouraged, since it is a misnomer. Oncocytic carcinoma is discussed as a distinct entity with the clear recognition that it refers to oncocytic follicular cell-derived neoplasms (composed of > 75% oncocytic cells) that lack characteristic nuclear features of PTC (those would be oncocytic PTCs) and high-grade features (necrosis and ≥ 5 mitoses per 2 mm2). High-grade follicular cell-derived malignancies now include both the traditional poorly differentiated carcinoma as well as high-grade differentiated thyroid carcinomas, since both are characterized by increased mitotic activity and tumor necrosis without anaplastic histology and clinically behave in a similar manner. Anaplastic thyroid carcinoma remains the most undifferentiated form; squamous cell carcinoma of the thyroid is now considered as a subtype of anaplastic carcinoma. Medullary thyroid carcinomas derived from thyroid C cells retain their distinct section, and there is a separate section for mixed tumors composed of both C cells and any follicular cell-derived malignancy. A grading system for medullary thyroid carcinomas is also introduced based on mitotic count, tumor necrosis, and Ki67 labeling index. A number of unusual neoplasms that occur in the thyroid have been placed into new sections based on their cytogenesis. Mucoepidermoid carcinoma and secretory carcinoma of the salivary gland type are now included in one section classified as "salivary gland-type carcinomas of the thyroid." Thymomas, thymic carcinomas and spindle epithelial tumor with thymus-like elements are classified as "thymic tumors within the thyroid." There remain several tumors whose cell lineage is unclear, and they are listed as such; these include sclerosing mucoepidermoid carcinoma with eosinophilia and cribriform-morular thyroid carcinoma. Another important addition is thyroblastoma, an unusual embryonal tumor associated with DICER1 mutations. As in all the WHO books in the 5th edition, mesenchymal and stromal tumors, hematolymphoid neoplasms, germ cell tumors, and metastatic malignancies are discussed separately. The current classification also emphasizes the value of biomarkers that may aid diagnosis and provide prognostic information.

Precursor and borderline lesions of the thyroid (indolent lesions of epithelial origin): from theory to practice.

The precursor lesions of thyroid neoplasms can arise from either C cells or follicular cells. Although MTC has an established and recognized precursor lesion, the C-cell hyperplasia, the same does not occur for the follicular cell-derived tumors, which are much more frequent. One of the significant obstacles to recognizing follicular cell-derived precursor lesions (FCPL) is the lack of refinement of the morphological spectrum and biology of these putative premalignant lesions. What are the "gold standard" histological criteria in thyroid pathology to identify the progression of dysplasia to cancer? Diagnostical irreproducibility and misnomer in the terminology of some FCPLs have been lying behind the answer to this question. The last past decades' advances in molecular pathology allow us to transform the knowledge in thyroid pathology to cancer prevention and early detection, which will only be possible by improving our understanding of the nature of thyroid precursor and borderline lesions. This review, amassed with the augmented expertise of thyroid pathology documented in the literature, is an attempt at underlining the present understanding of precursor and borderline lesions of the thyroid, with a particular highlight on practice differences in Asian and Western geographies.

Investigation of Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma at Hochiminh City Oncology Hospital

Abstract Introduction Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy. These areforms of follicular cell-derived tumors, and they have the capacity to catch iodine. The overall survival rates of metastatic or progressive differentiated thyroid carcinomaat 10 and 15years were 56% and 45% in cases of the radioiodine-avid tumor. The rates were only 10% and 6%at 10and 15 years respectively if the tumor becamenon-iodine avid.Identification ofthe iodine-refractorycriteria helps us treat properly. Patients and Methods a retrospective, cross-sectional descriptive analysis of radioactive iodine-refractory DTC conducted from January 2017 to December 2017. Data Processing and Analysis with SPSS 22.0 Results Forty-three in 1428 patients enrolled in the study from January 2017 to December 2017. About 50% of patients were T3-and T4 tumor,48.8% got N1b lymph nodes metastasis. Distal accounted for 50%, in which pulmonary, bone metastasis, and both were 66.7%, 23.8%, and 9.5%, respectively. The refractory rate was 3.0%, in which most of them belonged to group III (44.2%). Treatment followed by operation (11.6%), external radiotherapy ( 20.9%) and the others were followed up actively or treated Levothyroxinsuppression therapy and further radioactive iodine, aiming to palliative care and reduction of tumor burden.No patient administrated TKIstherapy. Conclusions The most of the refractory patients were elder and under the high-risk group of recurrence, in which mainly T4 tumor or locoregional invasion or distant metastasis. Identification of radioactive iodine-refractory criteria helps us treat properly. TKIs therapy in case of progression administrated recently.

Galectin-3 and HBME-1 Expression on Agarose Cell Blocks from Fine-needle aspirates of Follicular Cell-derived Thyroid Tumors.

Aim:To test the expression of galectin-3 (gal-3) and Hector Battifora mesothelial antigen-1 (HBME-1) on agarose cell blocks (CBs) of fine-needle aspirates aiming to determine their diagnostic value in thyroid follicle cell-derived tumors.Materials and Methods:Forty patients with thyroid nodule were enrolled. Fine-needle aspiration biopsy was done and processed to produce smears and CBs. Immune staining was done on CBs using antibodies to gal-3 and HBME-1. Diagnostic value of tests was determined in comparison to pathology.Results:Current study included 17 papillary thyroid carcinoma (PTC), 15 follicular adenoma, and 8 follicular thyroid carcinoma (FTC). In PTC diagnosis, co-expression of gal-3/HBME-1 had a sensitivity of 94.1%, specificity of 73.3%, positive predictive value (PPV) of 80%, negative predictive value (NPV) 91.7%, and accuracy of 84.4%. In FTC diagnosis, combined gal-3/HBME-1 expression had a sensitivity of 75%, specificity of 78.6%, PPV of 50%, NPV of 91.7%, and accuracy of 77.8%. Co-expression of gal-3/HBME-1 raised the sensitivity of detection of differentiated thyroid carcinomas from 40% with cytomorphology to 92% and accuracy from 62.5% to 85%.Conclusion:The combined immunocytochemical expression of gal-3 and HBME-1 utilizing fine-needle aspirates can improve the sensitivity of detection and diagnostic accuracy of differentiated follicular cell-derived thyroid carcinomas.

Hyalinizing trabecular tumor of the thyroid gland and its significant diagnostic issue

BackgroundHyalinizing trabecular tumors (HTT) are rare follicular cell-derived tumors of the thyroid gland that are infrequently reported in otolaryngology literature. We present here an interesting case of HTT which provides the basis for review of this entity’s clinical characteristics, criteria useful in making the diagnosis, and any currently available therapeutic modalities.Case presentationA 70-year-old Caucasian female underwent a CT scan of her chest and was incidentally found to have a nodule within the right thyroid lobe. Gross examination of the excised thyroid lobe revealed a circumscribed and encapsulated lesion (tan / gritty in texture), confined to the gland. Histologic sections of the lesion revealed a circumscribed neoplasm with a trabecular and organoid architecture associated with abundant dystrophic calcification. Neoplastic cells showed a spindled morphology with clumped chromatin and ample eosinophilic cytoplasm.ConclusionsHistologically, HTT is a follicular cell-derived tumor composed of neoplastic cells arranged in a trabecular pattern with hyalinization and calcification of extracellular material. Distinguishing features of HTT include minimal cytologic atypia with a low nuclear: cytoplasmic ratio, cellular aggregates around hyalinized material, and nuclei with clumped chromatin and occasional grooves and/or pseudoinclusions. Though debated in the literature, the general consensus is that this tumor is a benign entity. It is our hope that additional clinical research will elicit awareness of these rare tumors.

C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid.

- The identification of precursor or dysplastic lesions in the thyroid is difficult. Pathology of the C cell has been extensively studied, and the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinomas is well established. However, the distinction between neoplastic and physiologic/reactive C-cell hyperplasia remains a challenge. Unlike C cells, the existence of a precursor lesion of follicular cell-derived tumors is less well established, and a dysplastic or preneoplastic follicular lesion has not been well defined. - To discuss putative precursor lesions in the thyroid arising from C cells and follicular epithelial cells. - Data were obtained from a review of the pertinent peer-reviewed literature. - Although the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinoma is well recognized, the preneoplastic nature/malignant potential of reactive/physiologic C-cell hyperplasia and its role in the development of sporadic, medullary thyroid carcinoma is still unclear. Current data suggest that benign follicular lesions may have malignant potential, and there may be a multifocal progression from benign to malignant. Atypical follicular lesions in the background of chronic lymphocytic thyroiditis may represent dysplastic or premalignant lesions.

Differential expression of aquaporins and its diagnostic utility in thyroid cancer.

BackgroundAquaporin3 (AQP3) and Aquaporin4 (AQP4) play a major role in transcellular and transepithelial water movement as water channel membrane proteins. Little is known of their expression and significance in human thyroid tissues. Thus, we examined the expression of AQP3 and AQP4 in normal, hyperplastic and neoplastic thyroid tissues in conjunction with human thyroid cancer cell lines.Methods and ResultsImmunohistochemical analyses demonstrated AQP3 in the cytoplasmic membrane of normal C cells, but not in follicular cells. In contrast, AQP4 was not found in C cells but was identified in normal follicular cells. AQP4 was positive in 92% of Graves’ disease thyroids and 97% of multinodular goiters, and we failed to demonstrate AQP3 in these hyperplastic tissues. In neoplastic thyroid lesions, we observed AQP3 in 91% of medullary thyroid carcinomas but in no other follicular cell tumors. AQP4 was demonstrated in 100% of follicular adenomas, 90% of follicular carcinomas, and 85% of papillary carcinomas, while it was negative in all medullary carcinomas and undifferentiated carcinomas. Reverse transcriptase polymerase chain reaction (RT-PCR) analyses revealed AQP3 mRNA expression only in medullary carcinomas and AQP4 mRNA expression in follicular cell-derived tumors except for undifferentiated carcinomas. In thyroid cancer cell lines, using RT-PCR and western blotting, AQP3 mRNA and protein were only identified in the TT cell line (human medullary carcinoma cell line) and AQP4 in the other cell lines. In addition, AQP3 mRNA expression was up-regulated by FBS and calcium administration in both a dose and time dependent manner in TT cells.ConclusionThe differential expressions of AQP3 and AQP4 may reflect the biological nature and/or function of normal, hyperplastic, and neoplastic thyroid cells and additionally may have value in determining differential diagnoses of thyroid tumors.

Familial Follicular Cell-Derived Thyroid Carcinoma

Follicular cell-derived well-differentiated thyroid cancer, papillary (PTC) and follicular thyroid carcinomas comprise 95% of all thyroid malignancies. Familial follicular cell-derived well-differentiated thyroid cancers contribute 5% of cases. Such familial follicular cell-derived carcinomas or non-medullary thyroid carcinomas (NMTC) are divided into two clinical–pathological groups. The syndromic-associated group is composed of predominately non-thyroidal tumors and includes Pendred syndrome, Warner syndrome, Carney complex (CNC) type 1, PTEN-hamartoma tumor syndrome (PHTS; Cowden disease), and familial adenomatous polyposis (FAP)/Gardner syndrome. Other conditions with less established links to the development of follicular cell-derived tumors include ataxia–telangiectasia syndrome, McCune Albright syndrome, and Peutz–Jeghers syndrome. The final group encompasses syndromes typified by NMTC, as well as pure familial (f) PTC with or without oxyphilia, fPTC with multinodular goiter, and fPTC with papillary renal cell carcinoma. This heterogeneous group of diseases does not have the established genotype–phenotype correlations known as in the familial C-cell-derived tumors or medullary thyroid carcinomas (MTC). Clinicians should have the knowledge to identify the likelihood of a patient presenting with thyroid cancer having an additional underlying familial syndrome stemming from characteristics by examining morphological findings that would alert pathologists to recommend that patients undergo molecular genetic evaluation. This review discusses the clinical and pathological findings of patients with familial PTC, such as FAP, CNC, Werner syndrome, and Pendred syndrome, and the heterogeneous group of familial PTC.

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.

Thyroid Cancer of Follicular Cell Origin in Inherited Tumor Syndromes

Well-differentiated thyroid cancer accounts for 95% of thyroid malignancies. In contrast to medullary thyroid carcinoma, in which about 25% are familial, only 5% of follicular cell-derived thyroid carcinomas are a component of a familial cancer syndrome. The familial follicular cell-derived tumors or nonmedullary thyroid carcinoma encompass a heterogeneous group of diseases, and are classified into 2 distinct groups: syndromic-associated tumors, occurring in syndromes in which nonmedullary thyroid carcinomas are the predominant tumor encountered, and nonsyndromic tumors, those occurring in tumor syndromes in which thyroid involvement is a minor component. The first group, syndromic-associated tumors, includes phosphase and tensin (PTEN)-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis/Gardner syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome. Other syndromes, as McCune Albright syndrome, Peutz-Jeghers syndrome, and Ataxia-teleangiectasia syndrome may be associated with the development of follicular cell-derived tumors, but the link is less established than the above syndromes. The syndromic-associated tumors are the focus of this review. The second group of familial follicular cell-derived tumors syndromes or nonsyndromic tumors, in which nonmedullary thyroid carcinomas are the major findings, include pure familial papillary thyroid carcinoma, with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary thyroid carcinoma with multinodular goiter. This review will discuss the clinical and pathological findings of the patients with familial syndrome-associated tumors: PTEN-hamartoma tumor syndrome/Cowden syndrome, familial adenomatous polyposis syndrome, Carney complex type 1, Werner syndrome, and Pendred syndrome.

Targeted molecular therapies in thyroid carcinoma

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.

Expression of nestin mRNA is a differentiation marker in thyroid tumors

Nestin is a maker that identifies stem cells in some adult tissues, and its expression is believed to relate to malignancy in cancer cells. In this study, we measured the expression levels of nestin mRNA in various kinds of thyroid tumor by the real-time quantitative reverse transcription-polymerase chain reaction. Unexpectedly, nestin mRNA was detected in almost all differentiated thyroid tumors and normal thyroid tissues, whereas extremely decreased expression was observed in anaplastic carcinomas, which are the most malignant of the thyroid follicular cell-derived tumors. These results suggest that nestin mRNA is a differentiation marker, and its expression does not relate to malignant characteristics in thyroid tumors.

Familial Non-Medullary Thyroid Carcinoma: An Update

Familial thyroid cancer can arise from follicular cells (familial non-medullary thyroid carcinoma (FNMTC)) or from the calcitonin-producing C-cell (familial medullary thyroid carcinoma). This is usually a component of multiple endocrine neoplasias (MEN) 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. In contrast, the case for a familial predisposition of non-medullary thyroid carcinoma is only now beginning to emerge. Although the majority of papillary (PTC) and follicular thyroid carcinomas (FTC) are sporadic, familial tumors account for over 5% of cases. The presence of multifocal papillary carcinoma is a common feature of FNMTC. The familial follicular cell-derived tumors or non-medullary thyroid carcinomas encompass a heterogeneous group of diseases, including diverse syndromic-associated tumors and non-syndromic tumors. Based on clinico-pathologic findings, FNMTC is divided into two groups. The first includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis (FAP), PTEN hamartoma tumor syndrome (PHTS), Carney complex type 1, and Werner syndrome. The second group includes familial syndromes characterized by a predominance of NMTC, such as pure familial (f) PTC with or without oxyphilia, fPTC with papillary renal cell carcinoma, and fPTC with multinodular goiter. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetic evaluation.

Trefoil Factor 3 (TFF3): A Promising Indicator for Diagnosing Thyroid Follicular Carcinoma

Since the introduction of fine needle aspiration biopsy (FNAB) in the 1970's, a preoperative diagnostic technique for thyroid follicular carcinoma has long been awaited. Many markers that distinguish follicular carcinomas from adenomas have been reported; however, most of them have not been confirmed to be beneficial for clinical use. Trefoil factor 3 (TFF3) is a relatively new family of peptides that bears the three-loop trefoil domain. Several groups have reported that the suppression of TFF3 mRNA expression is related to malignant characteristics of thyroid follicular cell-derived tumors and the expression level of TFF3 mRNA is the most promising indicator for diagnosing follicular carcinoma. Development of TFF3-based diagnostic methods is now ongoing and it may not be long before thyroid follicular carcinoma can be diagnosed preoperatively using an aspirated sample from the tumor.

Follicular Thyroid Tumors with the PAX8-PPARγ1 Rearrangement Display Characteristic Genetic Alterations

Follicular thyroid carcinomas (FTC) arise through oncogenic pathways distinct from those involved in the papillary histotype. Recently, a t(2;3)(q13;p25) rearrangement, which juxtaposes the thyroid transcription factor PAX8 to the peroxisome proliferator-activated receptor (PPAR) gamma1, was described in FTCs. In this report, we describe gene expression in 11 normal tissues, 4 adenomas, and 8 FTCs, with or without the PAX8-PPARgamma1 translocation, using custom 60-mer oligonucleotide microarrays. Results were confirmed by quantitative real-time polymerase chain reaction of 65 thyroid tissues and by immunohistochemistry. Statistical analysis revealed a pattern of 93 genes discriminating FTCs, with or without the translocation, that were morphologically undistinguishable. Although the expression of thyroid-specific genes was detectable, none appeared to be differentially regulated between tumors with or without the translocation. Differentially expressed genes included genes related to lipid/glucose/amino acid metabolism, tumorigenesis, and angiogenesis. Surprisingly, several PPARgamma target genes were up-regulated in PAX8-PPARgamma-positive FTCs such as angiopoietin-like 4 and aquaporin 7. Moreover many genes involved in PAX8-PPARgamma expression profile presented a putative PPARgamma-promoter site, compatible with a direct activity of the fusion product. These data identify several differentially expressed genes, such as FGD3, that may serve as potential targets of PPARgamma and as members of novel molecular pathways involved in the development of thyroid carcinomas.