Follicular Cell-derived Thyroid Carcinomas Research Articles

Selpercatinib for treating recurrent mixed medullary and follicular cell-derived thyroid carcinoma: a case report

BackgroundMixed medullary and follicular cell-derived thyroid carcinoma (MMFCC) is characterized by the coexistence of follicular and C cell–derived tumour cell populations within the same lesion. Due to its rarity, its etiology and clinical course remain unclear, and treatment for advanced or recurrent cases has not been established.Case presentationWe report a case of MMFCC treated with selpercatinib. The patient was a 69-year-old male presenting with tumors in the right thyroid lobe and in the upper mediastinum. Fine-needle aspiration (FNA) cytology of the right thyroid lobe tumor revealed a medullary carcinoma; germline RET mutations were not detected. After resection of the right thyroid lobe with central node dissection, rapid intraoperative diagnosis of the mediastinal mass confirmed malignancy, leading to total thyroidectomy with excision of the upper mediastinal tumor. Histologically, the tumor in the right thyroid lobe and the pretracheal lymph node revealed a mixture of medullary and follicular carcinoma components, diagnosed as MMFCC. The mediastinal lymph node exhibited only medullary carcinoma components. At 11 months postoperatively, computed tomography scans showed enlargement of the right supraclavicular and upper mediastinal lymph nodes. FNA cytology of the right supraclavicular lymph node suggested the recurrence of medullary thyroid carcinoma. The gene panel testing (The Oncomine Dx Target Test Multi-CDx system®, Thermo Fisher SCIENTIFIC) of metastatic lymph node revealed RET somatic mutation (M918T). Treatment with selpercatinib was initiated, and both the cervical and mediastinal lymph nodes showed a reduction in size.ConclusionsWe report a rare case of selpercatinib use for MMFCC. Since RET mutations may occur frequently in MMFCC, selpercatinib could be effective in treating MMFCC.

Poorly differentiated thyroid carcinomas: conceptual controversy and clinical impact.

Poorly differentiated thyroid carcinomas (PDTC) are rare diseases; nevertheless, they account for the majority of deaths from non-anaplastic follicular cell-derived thyroid carcinomas. Establishing the diagnosis and treatment of PDTC is challenging given the low incidence and the lack of standardization of diagnostic criteria. These limitations hamper the ability to compare therapeutic modalities and outcomes between recent and older studies. Recently, the 5th edition of the classification of endocrine tumors has been published, which includes changes in nomenclature and the addition of the disease entity of "differentiatedhigh-grade follicular cell-derived carcinomas". On the other hand, the recently witnessed advances in molecular diagnostics have enriched therapeutic options and improved prognosis for patients. We herein review the various historical variations and evolution in the diagnostic criteria for PDTC. This systematic review attempts to clarify the evolution of the histological and molecular characteristics of this disease, its prognosis, as well as itstreatment options.

High Grade Differentiated Follicular Cell-Derived Thyroid Carcinoma Versus Poorly Differentiated Thyroid Carcinoma: A Clinicopathologic Analysis of 41 Cases.

Criteria overlap for separating between malignant follicular epithelial cell-derived thyroid gland neoplasms with high grade features of increased mitoses and tumor necrosis but lacking anaplastic histology. Patterns of growth, nuclear features, tumor necrosis, and various mitotic index cutoffs are suggested, but a reproducible Ki-67-based labeling index has not been established. Forty-one cases diagnosed as poorly differentiated thyroid carcinoma (PDTC) or high grade differentiated follicular cell-derived thyroid carcinoma (HGDFCDTC) were reviewed, with histologic features, mitotic figure counts, and Ki-67 labeling index reviewed on cases within Southern California Permanente Medical Group from 2010 to 2021 to establish any potential outcome differences. There were 17 HGDFCDTC (nine papillary thyroid carcinoma; eight oncocytic follicular thyroid carcinoma), median age 64years, affecting nine females and eight males. Tumors were large (median, 6.0cm), usually unifocal (n = 13), with only one tumor lacking invasion. Tumor necrosis was present in all; median mitotic count was 5/2 mm2 (median Ki-67 labeling index 8.3%). Three patients had metastatic disease at presentation, with additional metastases in four patients (41.2% developed metastases); 11 were without evidence of disease (median 21.2months); with the remaining six patients alive (n = 4) or dead (n = 2) with metastatic disease (median 25.8months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; age ≥ 55years; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. There were 24 PDTC, median age 57.5years, affecting 13 females and 11 males. Tumors were large (median, 6.9cm), with 50% part of multifocal disease, with three tumors lacking invasion. Insular/trabecular/solid architecture was seen in all tumors; tumor necrosis was present in 23; and median mitotic count was 6/2 mm2 (median Ki-67 labeling index 6.9%). Five patients had metastatic disease at presentation, with additional metastases in 3 patients (29.2% developed metastases); 16 were without evidence of disease (median, 48.1months); with the remaining 8 patients alive (n = 3) or dead (n = 5) with metastatic disease (median, 22.4months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. HGDFCDTC shows tumor necrosis, a median Ki-67 labeling index of 8.3%, with a high percentage (41%) of patients developing metastatic disease. Extent of invasion (non-invasive, minimally invasive, angioinvasive, widely invasive) correlates strongly with developing metastatic disease. PDTC presents at a slightly younger age, with large tumors, often in a background of multifocal tumors, with tumor necrosis nearly always seen, a median Ki-67 labeling index of 6.9%, with 29% of patients developing metastatic disease. Separation between groups is meaningful as early metastatic disease is relatively common, but mitotic counts/labeling indices are not different between the groups nor able to potentially risk stratify development of metastatic disease.

Thyroid Nodules and Follicular Cell-Derived Thyroid Carcinomas in Children.

Although pediatric thyroid tumors have many similarities to those occurring in adults, significant differences are also recognized. For example, although thyroid nodules in children are much less common than in adults, a higher percentage is malignant. Moreover, while pediatric papillary thyroid carcinoma (PTC) is associated with more advanced disease, death due to disease in children and adolescents is very rare, even when distant metastases are present. Some subtypes of thyroid carcinoma, like diffuse sclerosing variant, are especially common in children and adolescents. Moreover, certain histologic findings, such as a tall cell morphology or increased mitotic activity, may not carry the same prognostic significance in children as in adults. Recent studies exploring the molecular underpinnings of pediatric thyroid carcinoma indicate that while driver alterations of thyroid tumorigenesis in children and adults are essentially the same, they occur at very different frequencies, with translocation-associated tumors (most commonly harboring RET and NTRK fusions) comprising a sizable and distinct group of pediatric PTC. DICER1 mutations, an infrequent mutation in adult thyroid tumors, are relatively frequent in pediatric encapsulated follicular-patterned thyroid tumors (with or without invasion or nuclear features of PTC). Additionally, tumor predisposition syndromes (most notably DICER1 syndrome and PTEN hamartoma tumor syndromes such as Cowden syndrome) should be considered in children with thyroid tumors, especially follicular-patterned thyroid tumors and poorly differentiated thyroid carcinoma. This review will explore the current state of knowledge of thyroid nodules and carcinomas in children and adolescents.

Ultrasound evolution of parenchymal changes in the thyroid gland with autoimmune thyroiditis in children prior to the development of papillary thyroid carcinoma - a follow-up study.

Follicular cell-derived thyroid carcinoma represents the vast majority of paediatric thyroid cancers (TCs). Papillary thyroid carcinoma (PTC) accounts for over 90% of all childhood TC cases, and its incidence in paediatric patients is increasing. The objective of this follow-up study was to present the outcome of ultrasound (US) and laboratory monitoring of paediatric patients with autoimmune thyroiditis (AIT) prior to the development of PTC. This prospective study included 180 children and adolescents (132 females; 73.3%) with a suspicion of thyroid disorder referred to the Outpatient Endocrine Department. The patients were divided into four groups: 1) 28 patients with a mean age of 10.7 [standard deviation (SD), 3.1] y, in whom PTC was detected during the active surveillance of AIT [AIT(+), PTC(+) follow up (F)]; 2) 18 patients with a mean age of 12.8 (SD, 3.4) y, in whom PTC and AIT were detected upon admission (A) [AIT(+), PTC(+) A]; 3) 45 patients with a mean age of 13.0 (SD, 3.4) y, in whom PTC was detected upon admission and AIT was excluded [AIT(-), PTC(+) A]; and 4) an age- and sex-matched control group of 89 patients with AIT and with a mean age of 9.4 (SD, 3.0) y. The analysis included clinical, US, and laboratory assessment results of children on admission (groups 1-4) and during follow-up (groups 1 and 4) in the Paediatric Endocrine Outpatient Department. Upon admission of those in group 1, the US evaluation revealed a hypoechogenic thyroid gland in 12 and an irregular normoechogenic gland in 16 patients. US monitoring revealed an increase in thyroid echogenicity and an increased irregularity of the thyroid structure during the follow-up period of all of the patients from group 1. Such changes were not noticed in group 4. PTC was diagnosed at the mean time of 3.6 y (3 mo-9 y) since AIT confirmation in group 1. The mean maximum PTC diameter as per the US was significantly smaller in group 1 than in groups 2 and 3 [13.2 (10.8) mm vs. 22.2 (12.8) and 22.05 (15.4) mm]. Fewer patients in group 1 were referred to 131I than in groups 2 and 3 (71.4% vs. 94.4 and 93.3%). Interestingly, significant differences were observed in the thyroglobulin antibody (TgAb)/thyroid peroxidase antibody (TPOAb) ratio between groups 2 and 3, as opposed to group 4, at the beginning of observation [15.3 (27.6) and 3.5 (8.8] vs. 0.77 (1.9)]. In group 1, after the follow-up, an increase in the TgAb/TPOAb ratio was observed [1.2 (9.8) to 5.2 (13.5)]. There were no significant differences between groups 1-3 in labeling index Ki67, lymph nodes metastasis, extrathyroidal extension, and angioinvasion. There were no associations between thyroid-stimulating hormone, TgAb, and the extent of the disease. The use of thyroid US focused on the search for developing tumours in the routine follow-up of patients with AIT may not only help in the early detection of thyroid malignancies that are not clinically apparent but may also influence the invasiveness of oncological therapy and reduce the future side effects of 131I therapy. We propose that the repeat evaluation of TPOAb and TgAb warrants further exploration as a strategy to determine TC susceptibility in paediatric patients with AIT in larger multicentre studies.

Clinicopathologic and Prognostic Features of Pediatric Follicular Cell-Derived Thyroid Carcinomas: A Retrospective Study of 222 Patients

Clinical ThyroidologyVol. 35, No. 02 Pediatric ThyroidologyClinicopathologic and Prognostic Features of Pediatric Follicular Cell-Derived Thyroid Carcinomas: A Retrospective Study of 222 PatientsTheodora PappaTheodora Pappa Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston, MA, U.S.A. Head and Neck Oncology Cancer Treatment Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S.A.Search for more papers by this authorPublished Online:8 Feb 2023https://doi.org/10.1089/ct.2023;35.50-53AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 35Issue 02Feb 2023 Information© Copyright 2023, Mary Ann Liebert, Inc.To cite this article:Theodora Pappa.Clinicopathologic and Prognostic Features of Pediatric Follicular Cell-Derived Thyroid Carcinomas: A Retrospective Study of 222 Patients.Clinical Thyroidology.Feb 2023.50-53.http://doi.org/10.1089/ct.2023;35.50-53Published in Volume: 35 Issue 02: February 8, 2023PDF download

Advances in Thyroid Pathology: High Grade Follicular Cell-derived Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

In the upcoming World Health Organization fifth edition classification of endocrine tumors, there were several major changes related to high grade follicular-derived thyroid carcinoma (HGFCTC) and anaplastic thyroid carcinoma (ATC) based on emerging evidence about the diagnostic criteria clinical behavior, prognostic factors, and molecular signatures of these tumors. In this review, we aim to summarize the major evolutions of HGFCTC and ATC. HGFCTC is a nonanaplastic carcinoma with high grade features (High mitotic count, tumor necrosis). It is subdivided into poorly differentiated thyroid carcinoma diagnosed using the Turin proposal and differentiated high grade thyroid carcinoma. The latter is defined by the presence of the cytoarchitectutal features of well-differentiated thyroid carcinoma (eg, papillae) but harbors elevated mitotic activity and/or tumor necrosis. Poorly differentiated thyroid carcinoma is predominantly RAS -driven and associated with RAI avidity and high propensity for distant metastasis, whereas differentiated high grade thyroid carcinoma is mostly BRAFV600E -driven. ATC may show a wide range of histologic features. Carcinoma of pure squamous phenotype is associated with a high frequency of BRAF V600E mutations and is now considered as a subtype of ATC. There is a stepwise molecular progression from well-differentiated carcinoma to HGFCTC to ATC manifested by 1) early and persistent driver alteration in the MAPK pathway, particularly BRAF V600E and RAS mutations, and 2) gain of secondary aggressive molecular signatures (such as TERT promoter and TP53 mutations) when tumors progress from well-differentiated to high grade to anaplastic carcinoma.

Clinicopathologic and Prognostic Features of Pediatric Follicular Cell-derived Thyroid Carcinomas: A Retrospective Study of 222 Patients.

Pediatric thyroid carcinomas (TCs) are rare and mainly approached based on data extrapolated from adults. We retrospectively reviewed 222 pediatric TCs (patient age less than or equal to 21y). Lymph node (LN) disease volume at presentation was considered high if the largest positive LN measured ≥1cm and/or >5 LNs were positive. High-grade follicular cell-derived thyroid carcinoma (HGFCTC) were defined by the presence of marked mitotic count and/or tumor necrosis and considered as high-risk histology along with papillary thyroid carcinomas (PTC) diffuse sclerosing variant (DSV). Disease-free survival (DFS) was analyzed. LN involvement at presentation was significantly associated with male sex, larger tumor size, lymphatic invasion, positive surgical margins, and distant metastases at presentation. Five- and 10-year DFS was 84% and 77%, respectively. Only 1 patient with HGFCTC died of disease. Within PTC variants, PTC-DSV was associated with adverse histopathologic parameters and higher regional disease spread, unlike PTC tall cell variant which did not portend worse behavior. The presence of necrosis conferred worse DFS ( P =0.006), while increased mitotic activity did not. While the entire HGFCTC group did not correlate with outcome ( P =0.071), HGFCTC with necrosis imparted worse DFS ( P =0.006). When restricted to PTC-DSV and HGFCTC with necrosis, high-risk histologic classification emerged as an independent prognostic parameter of DFS ( P =0.020). The excellent prognosis of pediatric TCs differs from that of adult TCs showing similar histologic features. While neither increased mitotic activity nor PTC tall cell variant histology predict adverse outcome, PTC-DSV and tumors with necrosis constitute high-risk histologic variants with an increased risk of protracted disease.

NUTM1 -rearranged Carcinoma of the Thyroid : A Distinct Subset of NUT Carcinoma Characterized by Frequent NSD3 - NUTM1 Fusions.

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.

Expression of T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT) in anaplastic thyroid carcinoma

BackgroundImmune checkpoint proteins have not been fully examined in follicular cell-derived thyroid carcinoma and medullary thyroid carcinoma (MTC). Anaplastic thyroid carcinoma (ATC) is one of the most aggressive carcinomas. Even multimodal treatment does not result in favorable clinical outcomes for patients with ATC. Anti-tumor immunity has therefore been highlighted as having therapeutic promise for ATC.MethodsWe examined a novel immune checkpoint receptor, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domains (TIGIT), in variable thyroid lesions: adenomatous goiter, follicular adenoma, and thyroid carcinoma (TC) using immunohistochemistry (IHC).ResultsOur IHC results showed that TIGIT expression was detected in cancer cells of MTC and high-grade TC: poorly differentiated thyroid carcinoma (PDTC) and ATC. Neoplastic cells were positive for TIGIT in four of five MTCs (80.0%), 17 of 31 ATCs (54.8%) and in 3 of 12 PDTCs (25.0%). TIGIT was not detected in any adenomatous goiters, thyroid benign tumors, or differentiated thyroid carcinoma (DTCs). Intriguingly, ATC cells showing pleomorphic/giant cell features were positive for TIGIT, while ATC cells with other cell morphologies lacked the immunoreactivity. Intra-tumoral immune cell was inclined to be enriched in TIGI-positive ATC. Although coexisting papillary thyroid carcinoma (PTC) components demonstrated high-grade microscopic features, neither the PTC nor follicular thyroid carcinoma (FTC) components expressed TIGT in any composite ATCs.ConclusionTIGIT was immunohistochemically found in MTC with high frequency and partially in high-grade TC. TIGIT expression in cancer cells may be beneficial for a potential utility in MTC and a subset of high-grade TC, especially ATC therapy.

Aggressive variants of follicular cell-derived thyroid carcinoma: an overview.

The incidence of thyroid carcinoma has increased globally in the past years. Papillary thyroid carcinoma (PTC) is the most frequent neoplasm of the thyroid gland comprehending the 90% of the thyroid carcinoma and has an indolent clinical behaviour. However, some variants of follicular cell-derived thyroid carcinoma, including variants of classic of PTC, have been identified that show a more aggressive biological behaviour. An accurate diagnosis of these entities is crucial for planning a more aggressive treatment and improving patients' prognosis of patients. The aim of this review is to present the main clinical, histological, and molecular features of aggressive variants of follicular cell-derived thyroid carcinoma, and to provide useful histological parameters for determining the most suitable therapeutic strategy for patients affected by these forms. Variants of classic PTC such as the diffuse sclerosing variant (DSV), the tall cell variant (TCV), the columnar cell variant (CCV), the solid/trabecular variant (STV) and the hobnail variant (HV), and other variants of follicular cell-derived thyroid carcinoma, such as poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), are associated with aggressive behaviour. The correct identification and diagnosis of aggressive variants of follicular cell-derived thyroid carcinoma is important, as they allow the clinician to adopt the most refined therapeutic strategies in order to the survival of the patients.

Follicular Cell Derived Thyroid Carcinoma: Common Things Present in Uncommon Ways

Follicular cell derived thyroid carcinomas, including papillary thyroid carcinoma and follicular thyroid carcinoma, are common in daily pathology practice and the incidence of this entity is dramatically increased due to the wide application of more sensitive diagnostic procedures. However, uncommon presentations of thyroid cancers can be seen occasionally and without awareness of those scenarios, traps, and pitfalls that can easily compromise the patient's care. We reviewed the English literature through PubMed search based on three uncommon presentations identified during our routine diagnostic service for patients with or without thyroid nodules: (1) Phosphatase and tensin homolog immunoreactivity loss initially identified on common follicular nodules, and follicular thyroid carcinoma leading to the identification of a phosphatase and tensin homolog hamartoma tumor syndrome, (2) metastatic thyroid carcinoma incidentally identified in the specimens of neck lymph node dissection of head and neck squamous cell carcinoma, and (3) a papillary thyroid carcinoma incidentally identified in the specimen of laterally located thyroglossal duct cyst. We discussed the representative case scenarios, which include clinicopathologic, immunophenotypic, some with genomic features, diagnostic pearls, and patient management. Follicular cell-derived thyroid carcinoma is commonly diagnosed at a younger age than most other adult cancers. The awareness of those pitfalls would significantly improve the diagnostic accuracy leading to better patient outcomes.

Expanding the spectrum of thyroid carcinoma with somatic DICER1 mutation: a survey of 829 thyroid carcinomas using MSK-IMPACT next-generation sequencing platform.

DICER1 gene encodes an RNaseIII endoribonuclease essential for the cleavage of pre-microRNA to mature microRNA. Germline DICER1 mutation results in DICER syndrome, a cancer predisposition syndrome which manifests in the thyroid gland as early-onset multinodular goiter and increased risk for differentiated thyroid carcinoma. Recently, somatic DICER1 mutations were described in various thyroid neoplasms, including follicular adenoma, papillary thyroid carcinoma, follicular carcinoma, and poorly differentiated thyroid carcinoma. In this study, we identified and described 14 cases (1.7%) with somatic DICER1 mutations from a cohort of 829 patients with thyroid follicular cell-derived thyroid carcinomas which were sequenced using MSK-IMPACT targeted next-generation sequencing platform. We expanded the histologic spectrum of thyroid carcinomas with somatic DICER1 mutations to include Hurthle cell carcinoma, high-grade differentiated thyroid carcinoma, and anaplastic thyroid carcinoma. All patients were adults with a median age of diagnosis of 59years (range: 22-82). Although rare, a subset of thyroid cancers, including the aggressive subtypes, display somatic DICER1 mutations, some of which have oncogenic potential.

Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis.

Tumors with papillary cribriform and morular architecture were initially considered to be variants of papillary thyroid carcinoma; however, recent observations have challenged this view. In this study, we reviewed the demographical, histopathological, and immunohistochemical features of the largest case series, consisting of 33 tumors. The age at time of pathological diagnosis ranged from 18 to 59 (mean 33) years, and all patients except one were female. Sixteen patients had multifocal and fifteen had unifocal disease. The status of focality was unavailable in two patients.Tumors were well-circumscribed, ranging in size from 0.1 to 8.0cm. The cribriform component was admixed with morulae in the majority, except seven had a cribriform-predominant architecture and two had predominantly solid growth. Variable degrees of nuclear enlargement, elongation, overlapping, and grooves were seen but florid nuclear convolution, intranuclear pseudoinclusions, and optically clear nuclei due to chromatin margination were not appreciated. There was no or little colloid material within the cribriform spaces. Two solid tumors had high-grade features. Immunohistochemical studies showed beta-catenin nuclear and cytoplasmic positivity in all cases. The cribriform component was positive for TTF1 and negative for thyroglobulin. PAX8 was absent in half of these tumors and focal in the remainder. Morulae were positive for keratin 5 and CD5 and negative for p63, p40, TTF1, and PAX8. Molecular studies revealed germline APC mutations in 12 tumors and were negative in 5 sporadic tumors in a subset of tested tumors. Irrespective of the antibody used in this cohort, all cribriform-morular carcinomas express TTF1; however, PAX8 immunoreactivity is weak, focal or negative, and all tumors lack thyroglobulin reactivity; these findings raise questions about tumor cell origin and may indicate that these are not of thyroid follicular epithelial differentiation. We postulate that morulae may represent divergent thymic/ultimobranchial pouch-related differentiation. Given their unique cytomorphology, immunohistochemical profiles, and genetic features that have little overlap with traditional follicular cell-derived thyroid carcinomas, we propose that these tumors represent a distinct form of thyroid carcinoma unrelated to other neoplasms of thyroid follicular cells.

Correlation of molecular data with histopathological and clinical features in a series of 66 patients with medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) displays a wide variety of histopathological features, and several histological variants have been described. In follicular cell-derived thyroid carcinomas, there is a good correlation between genotype and phenotype. In this study, we investigated whether such a correlation is also present in MTC. The histopathological features were evaluated in a series of 66 molecularly characterised tumours and correlated with the clinical characteristics. Most MTC exhibited the classical variant (83.3%). Other variants included spindle cell (6.1%), pseudopapillary (4.5%), paraganglioma-like (3.0%), angiosarcoma-like (1.5%), and oncocytic follicular (1.5%). Tumours were classified into four groups: group 1, with somatic p.Met918Thr and p.Ala883Phe RET mutations; group 2, with other RET mutations; group 3, with RAS mutations; and group 4, without RET or RAS mutations. Tumours from groups 1 and 4 were typically associated with the classical variant, with abundant fibrosis, lymphovascular invasion, extrathyroidal extension, and more advanced stages of disease, whereas group 2 included histological variants other than the classical variant (namely, pseudopapillary and paraganglioma-like), with tumours that were highly cellular, less invasive, and with a better overall prognosis. In tumours from group 4, amyloid deposition was characteristically absent or low. The spindle cell variant appeared only in tumours from group 3, which had high cellularity and a degree of invasion and prognosis intermediate between groups 1 and 2, but better than group 4. The grade of fibrosis correlated directly with the clinical outcome. Our results support the idea that a genotype-phenotype correlation does, indeed, exist in MTC. However, further studies are warranted to confirm these findings in a larger sample size.

Clinicopathological Characteristics and Prognosis of Poorly Differentiated Thyroid Carcinoma Diagnosed According to the Turin Criteria

ObjectivePoorly differentiated thyroid carcinoma (PDTC) is the primary cause of death in patients with nonanaplastic follicular cell-derived thyroid carcinoma. We purposed to identify the clinical and pathological characteristics of PDTC and their relationship with prognosis. MethodsA retrospective analysis was conducted on patients diagnosed with PDTC at our institution from 2010 to 2018. All of their histopathology slides were reviewed by 2 experienced pathologists based on the Turin criteria. Furthermore, information regarding clinical characteristics, pathological characteristics, treatment strategy, and follow-up events were collected. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare survival curves. Then, the Cox proportional hazards model was used to perform univariate and multivariate analyses. ResultsTwenty-six patients with PDTC who met the Turin criteria were enrolled in this study. The median follow-up period of the included 26 patients was 76 months, while the 3- and 5-year survival rates were 40% and 18%, respectively. Notably, univariate analysis revealed that tumor size >4 cm (P = .038), extrathyroidal extension (ETE) (P = .020), distant metastases (P = .047), poorly differentiated areas >60% (P = .049), and Ki-67 labeling index >30% (P = .040) were associated with poor prognosis. On the other hand, multivariate analysis identified ETE (P = .007) and distant metastases (P = .031) as independent risk factors for poor prognosis. ConclusionPDTC is a rare carcinoma with high invasiveness and poor prognosis. Patients with ETE or distant metastases may have adverse outcomes.

S616-p-DRP1 associates with locally invasive behavior of follicular cell-derived thyroid carcinoma.

Dynamin-related protein 1 (DRP1), a mitochondrial fission protein, and its active form phosphorylated at Serine 616 (S616-p-DRP1) have been increasingly associated with tumorigenesis and invasion in various tumor models, including oncocytic thyroid cancer (TC). In this study, the expression of DRP1 and S616-p-DRP1 and its relationship with patients' clinicopathological characteristics, tumor genetic profiles, and clinical outcomes were assessed in a large series of follicular cell-derived TC (FCDTC). Retrospective biomarker study characterizing the clinicopathological and immunochemistry DRP1 and S616-p-DRP1 expression of a series of 259 patients with FCDTC followed in two University Hospitals. DRP1 expression was positive in 65.3% (169/259) of the cases, while the expression of the S616-p-DRP1 was positive in only 17.3% (17/98). DRP1-positive expression was significantly associated with differentiated tumors (67.7 vs. 48.0%; P = 0.049), non-encapsulated tumors (73.8 vs. 57.4%; P = 0.011) and thyroid capsule invasion (73.4 vs. 57.5%; P = 0.013). S616-p-DRP1-positive expression was significantly associated with tumor infiltrative margins (88.9 vs. 11.1%; P = 0.033), thyroid capsule invasion (29.8 vs. 3.1%; P = 0.043), lymph node metastases (23.3 vs. 8.1%; P = 0.012), and higher mean cumulative radioiodine dosage (317.4 ± 265.0 mCi vs. 202.5 ± 217.7 mCi; P = 0.038). S616-p-DRP1 expression was negatively associated with oncocytic phenotype (0.0 vs. 26.2%; P = 0.028). S616-p-DRP1 is a better candidate than DRP1 to identify tumors with locally invasive behavior. Prospective studies should be pursued to assess S616-p-DRP1 role as a molecular marker of malignancy in TC and in patients' risk assessment.

Pleural effusion as a novel prognostic factor in metastatic thyroid carcinoma.

Objective:To identify novel prognostic risk factors and compare them with other known prognostic risk factors in follicular-cell-derived thyroid carcinoma (FDTC) with distant metastases.Methods:A retrospective review was conducted of adult patients with metastatic FDTC seen at a tertiary care center between January 1990 and December 2010. A 15-year Kaplan–Meier survival estimate was created for overall survival (OS) and cancer-specific survival (CSS). Hazard ratios (HR) and P values from Cox proportional hazard models were used with a 95% CI.Results:There were 143 patients (60.1% male, 39.9% female), of whom 104 (72.7%) patients had papillary, 30 (21.0%) had follicular, 5 (3.5%) had poorly differentiated, and 4 (2.8%) had Hürthle cell cancers. Median length of follow-up was 80.0 months (range 1.0–564.0). The 15-year mortality rate was 32.2% and cancer-specific mortality was 25.2%, with OS and CSS having the same risk factors. Lung was the most common site of metastases in 53 patients (37.1%), and patients with pleural effusions had significantly lower CSS (HR = 5.21, CI = 1.79–15.12). Additional risk factors for a decreased CSS included: older age upon diagnosis (>45 years, HR = 4.15, CI = 1.43–12.02), multiple metastatic locations (HR = 3.75, CI = 1.32–10.67), and incomplete/unknown tumor resection (HR = 2.35, CI = 1.18–4.67).Conclusion:This study is the first to demonstrate that pleural effusion is a poor prognostic sign in patients with FDTC with distant metastases and compare this risk with other accepted prognostic variables.

SUN-474 An Unusual Case of Poorly Differentiated Thyroid Carcinoma with an Excellent Prognosis

Background: Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive subtype with morphological/behavioral features between differentiated thyroid carcinoma (DTC) and anaplastic thyroid carcinoma (ATC). Clinical case: A 43-year-old female presented with 3 cm right thyroid mass noted on US neck. FNA biopsy showed undifferentiated carcinoma, large cell type. Additional immune-stains were suggestive of ATC. Pre-surgery non-stimulated thyroglobulin (NSTG) was 311 (RR 0–55 ng/dl). Pathology post-total thyroidectomy with bilateral level VI lymph node dissection showed a 3.2 x 2.5 x 2.5 cm carcinoma with vascular and capsular invasion. Most of the mass consisted of very atypical pleomorphic cells, mitosis was difficult to find. The tumor did not show the widely invasive-destructive pattern commonly seen in ATC. An adjacent differentiated component showed predominantly follicular pattern and was described as dedifferentiated follicular carcinoma. All lymph nodes were negative for metastatic disease. Post-surgery NSTG was <0.2 (RR <0.1ng/ml as athyreotic), stimulated TG was 2.22 with negative TG antibodies. Four months later, she received 193.5 mCi radioactive iodine (RAI) therapy. The post-therapy scan showed no Iodine-131 avid uptake in neck or distant metastasis. Neck imaging and TG levels done periodically showed no structural or biochemical evidence of recurrence. Currently the patient is cancer-free for 14 years since diagnosis with no need for additional therapies. Discussion: PDTC accounts for 1–15% of all thyroid cancers. Although PDTC is rare, it is a clinically significant histological diagnosis as it represents the main cause of death from non-anaplastic follicular cell-derived thyroid carcinoma. The Turin proposal published in 2007 suggested three criteria for the diagnosis of PDTC which included the pattern of growth and high-grade features. PDTC presents more frequently with locally invasive extra-thyroidal disease, metastasis to regional lymph nodes and distant organs compared to DTC. Despite the capacity to have RAI uptake, there has been no evidence of significant improvement in survival due to tumor heterogeneity in differentiation. Recent data suggest that age more than 45 years, tumor size more than 4cm, extra-thyroidal extension, higher pathological T stage, positive margins, and distant metastasis predict worse prognosis. Conclusion: Our patient showed an excellent response to therapy in spite of having PDTC with positive margins. We hypothesize that this could be likely due to young age at the time of diagnosis, early detection of tumor while it was localized in the thyroid without distant metastasis as well as heterogeneity in the tumor with differentiated cells that are responsive to RAI. We conclude that with early detection, timely surgery, and adjuvant therapy, excellent prognosis can be achieved in patients with PDTC.

Poorly differentiated thyroid carcinoma

Poorly differentiated thyroid carcinoma (PDTC) is an aggressive form of follicular cell derived thyroid carcinoma with a prognosis intermediate between the indolent well differentiated thyroid carcinomas and the rapidly growing often fatal anaplastic carcinoma. While all investigators agree on the presence of this entity, there is disagreement in regard to its definition. In 2006, a set of criteria based solely on mitotic index ≥5/10 high power fields and/or tumor necrosis was proposed by a group of researchers from Memorial Sloan Kettering Cancer Center (MSKCC criteria) in New York. A year later, alternative diagnostic criteria of PDTC, so called the Turin proposal, were advocated by an international consensus group. The Turin proposal requires three criteria: 1) solid/trabecular/insular growth pattern; 2) absence of nuclear features of papillary carcinoma; and 3) at least one of the following three features: mitotic index ≥3/10 high power fields (HPFs), necrosis, or convoluted nuclei. In this review, we summarize the histology, diagnostic criteria (Turin proposal and MSKCC criteria) with their pros and cons, the prognostic factors, and molecular profile of PDTC, aiming to provide a practical and compreshensive review of this challenging entity.