Poorly Differentiated Thyroid Carcinoma Research Articles

Interpretation of the pathological diagnostic criteria and characteristics of high-grade thyroid follicular-derived carcinoma in the 5th edition WHO classification

The 5th edition WHO classification of thyroid tumors proposed high-grade non-anaplastic thyroid carcinoma, which includes traditional poorly differentiated thyroid carcinoma (PDTC) and differentiated high-grade thyroid carcinoma (DHGTC), with a prognosis between highly differentiated thyroid carcinoma and anaplastic thyroid carcinoma (ATC), in which about 50% of patients do not take radioactive iodine. Therefore, this classification is of great clinical significance. This article interprets the diagnostic criteria and genetic features of high-grade non-anaplastic thyroid carcinoma in 5th edition WHO classification, comparing with ATC.

Molecular Pathology of Thyroid Tumors: Essential Points to Comprehend Regarding the Latest WHO Classification.

In 2022, the new WHO Classification of Endocrine and Neuroendocrine Tumors, Fifth Edition (beta version) (WHO 5th), was published. Large-scale genomic analyses such as The Cancer Genome Atlas (TCGA) have revealed the importance of understanding the molecular genetics of thyroid tumors. Consequently, the WHO 5th was fundamentally revised, resulting in a systematic classification based on the cell of origin of tumors and their clinical risk. This paper outlines the following critical points of the WHO 5th. 1. Genetic mutations in follicular cell-derived neoplasms (FDNs) highlight the role of mutations in the MAP kinase pathway, including RET, RAS, and BRAF, as drivers of carcinogenesis. Differentiated thyroid cancers such as follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) have specific genetic alterations that correlate with morphological classifications: RAS-like tumors (RLTs) and BRAF p.V600E-like tumors (BLTs), respectively. 2. The framework for benign lesions has been revised. The WHO 5th introduces a new category: "developmental abnormalities". Benign FDNs comprise "thyroid follicular nodular disease", follicular thyroid adenoma (FTA), FTA with papillary architecture, and oncocytic adenoma (OA). "Hürthle cell adenoma/carcinoma" is renamed oncocytic adenoma/carcinoma of the thyroid (OA/OCA), which can be distinguished from FTA/FTC by its unique genetic background. 3. Low-risk tumors include NIFTP, TT-UMP, and HTT, and they have an extremely low malignant potential or an uncertain malignant potential. 4. PTC histological variants are reclassified as "subtypes" in the WHO 5th. 5. The concept of high-grade carcinomas is introduced, encompassing poorly differentiated thyroid carcinoma (PDTC), differentiated high-grade thyroid carcinoma (DHGTC), and high-grade medullary thyroid carcinoma (MTC). 6. Squamous cell carcinoma is included in anaplastic thyroid carcinoma (ATC) in the WHO 5th due to their shared genetic and prognostic features. 7. Other miscellaneous tumors are categorized as salivary-gland-type carcinomas of the thyroid, thyroid tumors of uncertain histogenesis, thymic tumors within the thyroid, and embryonal thyroid neoplasms. The WHO 5th thus emphasizes the importance of classifying tumors based on both genetic abnormalities and histomorphology. This approach aids in achieving accurate pathological diagnosis and facilitates the early selection of appropriate treatment options, including molecular targeted therapies.

Current evidences in poorly differentiated thyroid carcinoma: a systematic review and subsection meta-analysis for clinical decision making.

Poorly differentiated thyroid carcinoma (PDTC) is a distinct entity with intermediate prognosis between indolent follicular thyroid cancers and anaplastic carcinoma. The management guidelines are not standardized for these cancers due its low prevalence and limited available literature. Therefore, we did this systematic review with emphasis on current evidence on diagnosis, imaging, molecular markers, and management of these carcinomas. We searched four databases, PubMed, Medline, EMBASE, and Emcare to identify studies published till October 2023. All studies reporting diagnostic tests, imaging, molecular marker expression and management of PDTC were included in the review. The meta-analysis was conducted on expression of molecular markers in these cancers following recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Random-effects meta-analysis was used to calculate pooled estimated prevalence with 95% confidence intervals. Based on the inclusion criteria, 62 articles were selected to be incorporated for the review. Differences in pathological diagnostic criteria of PDTC was noted in literature which was addressed in WHO 2022 diagnostic terminologies with expansion of the definition. Surgical management is uniformly recommended for early stage PDTC. However, literature is divided and anecdotal for recommendations on radioactive iodine (RAI), extent of neck dissection and adjuvant treatment in PDTC. Evidence for Next Generation Sequencing (NGS), novel theragnostic approaches, immunotherapy targets are evolving. Based on the subset analysis for expression of molecular markers, we found the most common markers expressed were TERT (41%), BRAF (28%) and P 53 (25%). Poorly differentiated thyroid carcinomas have a high case fatality rate (up to 31%). Eighty-five % of the patients who succumb to the disease have distant metastasis. Even though under-represented in literature, evidence-based management of these aggressive tumors can help personalize the treatment for optimal outcomes.

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.

Anaplastic and poorly differentiated thyroid carcinomas: genetic evidence of high-grade transformation from differentiated thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most advanced and aggressive thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) lacks anaplastic histology but has lost architectural and cytologic differentiation. Only a few studies have focused on the genetic relationship between the two advanced carcinomas and coexisting differentiated thyroid carcinomas (DTCs). In the present study, we investigated clinicopathologic features and genetic profiles in 57 ATC and PDTC samples, among which 33 cases had concomitant DTC components or DTC history. We performed immunohistochemistry for BRAF V600E, p53, and PD-L1 expression, Sanger sequencing for TERT promoter and RAS mutations, and fluorescence in situ hybridization for ALK and RET rearrangements. We found that ATCs and PDTCs shared similar gene alterations to their coexisting DTCs, and most DTCs were aggressive subtypes harboring frequent TERT promoter mutations. A significantly higher proportion of ATCs expressed p53 and PD-L1, and a lower proportion expressed PAX-8 and TTF-1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs.

The frequency of mutations in advanced thyroid cancer in Japan: a single-center study.

We analyzed the outcomes of genetic testing to study the frequency of mutations in advanced thyroid cancer in Japan. Patients (n = 96) with unresectable or metastatic thyroid carcinoma were included for retrospective chart review. Results of gene panel testing, which was performed between May 2020 and April 2023, were analyzed. The median age of the patients was 73.5 years (range, 17-88); 59 were women, and 39 were men. Overall, 17 patients had anaplastic thyroid carcinoma (ATC), 68 had papillary thyroid carcinoma (PTC), 7 had follicular thyroid carcinoma, and 6 had poorly differentiated thyroid carcinoma (PDTC). Of the 81 patients with differentiated thyroid carcinoma (DTC) and PDTC, 88.9% were radioactive iodine-refractory, and 32.7% of all cases had previously been treated with multiple kinase inhibitors. Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion. Of PTC cases, 83.1% had BRAF mutations, 9.2% had RET fusion, and 1.5% had NTRK fusion. One case each of ATC and PTC had a tumor mutation burden of ≥10. ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%), whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference. In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options.

Genomic profiling of primary and metastatic thyroid cancers.

The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.

Characterization of the genomic alterations in poorly differentiated thyroid cancer

Poorly differentiated thyroid carcinoma (PDTC) is a subtype of thyroid cancer that has a high rate of metastasis or recurrence and a relatively poor prognosis. However, there are few studies that have been conducted on PDTC at the whole protein-coding gene scale. Here, we performed genomic profiling of 15 patients with PDTC originated from follicular thyroid carcinoma using whole exome sequencing and also performed gene functional enrichment analysis of differentially expressed genes (DEGs) for three patients. Further, we investigated genetic variants associated with PDTC progression and the characteristics of clinical pathology. We revealed somatic genomic alterations in the RAF1, MAP2K2, and AKT2 genes that were not reported in previous studies. We confirmed frequent occurrences in the RAS gene in patients with PDTC; the genetic alterations were associated with the RAS-RAF-MEK-ERK/JNK, PI3K-AKT-mTOR signaling pathways, and the cell cycle. DEG analysis showed that immune response was lower in cancer tissues than in normal tissues. Through the association analysis of somatic mutations and the characteristics of clinical pathology from patients with PDTC, the somatic mutations of ABCA12, CLIP1, and ATP13A3 were significantly associated with a vascular invasion phenotype. By providing molecular genetic insight on PDTC, this study may contribute to the discovery of novel therapeutic target candidates.

SAT538 Thyrotoxicosis in the Setting of Metastatic Poorly Differentiated Thyroid Carcinoma, a Marker of Disease Progression?

Abstract Disclosure: B.L. Chang: None. M.A. Fernandez: None. K.M. Shikuma Lee: None. Background: Thyrotoxicosis is a rare manifestation of thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) causing thyrotoxicosis has even more rarely been reported. Here, we report a case of PDTC with thyrotoxicosis developing in a previously euthyroid individual with longstanding untreated follicular neoplasm. Clinical Case: A 79-year-old veteran presented to routine endocrine follow up with new symptoms of thyrotoxicosis. Although previously euthyroid, the evaluation revealed new findings of low serum thyrotropin (TSH) (&amp;lt;0.01 uIU/mL, n=0.34 – 5.60 uIU/mL), elevated free thyroxine (FT4) (2.6 ng/dL, n=0.58 – 1.64 ng/dL), and high total T3 (TT3) levels (223 ng/dL, n=76 – 181 ng/dL). Thyroid stimulating immunoglobulin antibodies (TSI) were positive (214, n&amp;lt;140). Patient has a nine-year history of a fine needle aspiration (FNA) of a large right-sided thyroid nodule with cytology suspicious for follicular neoplasm but declined surgical removal. Thyroid uptake and scan showed heterogeneous uptake throughout the right lobe with a relative photopenic region centrally and spots of more increased activity in areas within the right lobe. The left thyroid lobe showed uniformly low uptake. PET-CT evaluation confirmed spotty FDG-avid areas within the right thyroid mass but did not show other areas of hyperactivity. Methimazole was started with clinical and biochemical improvement. Patient underwent total thyroidectomy, and histopathologic examination showed PDTC with extensive angioinvasion involving the majority of the right thyroid lobe with the left lobe containing a mix of benign thyroid tissue and PDTC fragments. Areas of hyperintensity on the uptake scan correlated to pathological PDTC locations within the right lobe. Within three weeks of thyroidectomy, patient developed recurrent hyperthyroidism. Laboratory studies showed low TSH (0.04 uIU/mL) and elevated FT4 (2 ng/dL). In contrast to pre-operative studies, repeat TSI was below the reference range. Levothyroxine (LT4) was held in anticipation of radioactive iodine therapy, but four weeks later the TSH remained suppressed. 131I was administered which showed accumulation within small thyroid remnants and a single left level three 131I-avid lymph node without other metastases. Following 131I treatment, patient returned to a euthyroid state on standard LT4. Conclusion: Hyperthyroidism has rarely been associated with PDTC, although previous reports have linked more aggressive, multifocal, and locally invasive thyroid cancers to concurrent Graves’ disease or productive bulky metastatic disease. Even without bulky metastatic disease, clinicians should be aware that hyperproductivity may indicate development of autoimmune thyrotoxicosis within PDTC. Presentation Date: Saturday, June 17, 2023

THU510 The Frequency Of Mutations In Advanced Thyroid Cancer In Japan: A Real Clinical Setting

Abstract Disclosure: S. Toda: None. A. Takahashi: None. K. Masudo: None. H. Iwasaki: None. Background: Thyroid cancer has a high incidence of actionable genetic alterations, but the frequency of mutations in advanced thyroid cancer that requires drug therapy is unknown. Therefore, we examined the outcomes of genetic testing performed in a real clinical setting for the purpose of pharmacotherapy. Methods: In Japan, Oncomine Dx is approved for thyroid cancer that requires drug therapy, and comprehensive genomic profiling is approved for anaplastic thyroid carcinoma and other thyroid carcinomas after the induction of tyrosine kinase inhibitors. We retrospectively reviewed the cases of those who had their tests performed between 2020 and 2022. Results: The study included 65 patients, and the testing methods used were Oncomine Dx in 36 cases, FoundationOne in 25 cases, and FoundationOne Liquid in 4 cases. With a median age of 74 years (range 17–86), 42 were female and 23 were male. Moreover, 13 cases had anaplastic thyroid carcinoma (ATC), 4 follicular thyroid carcinoma (FTC), 42 papillary thyroid carcinoma (PTC), and 6 poorly differentiated thyroid carcinoma (PDTC). Of the PTC examined by Oncomine Dx, 96.8% (30/31) were RAI-refractory; all comprehensive genomic profiling testing cases except ATC had previously been treated with tyrosine kinase inhibitors. In the following cases, actionable mutations were observed. Among 13 ATC cases, 46.2% (6) had BRAF mutation and 7.7% (1) had RET fusion. Of 42 PTC cases, 85.7% (36) had BRAF mutation and 7.1% (3) had RET fusion. Of 6 PDTC cases, 33.3% (2) had BRAF mutation and 16.7% (1) had RET fusion. No actionable mutations were observed in FTC (0/4). We found one case each of ATC and PTC with tumor mutation burden of 10 or higher, both with BRAF mutation. NTRK fusion was not observed in any of the 65 patients studied. There were four PTC cases (9.5%) with iodine accumulation in metastases, two with BRAF mutations, one with RET fusion, and one without detectable mutations. Comparing mutations in ATC and non-ATC, TERT promoter mutations were found in 84.6% of ATC (11/13) vs. 56.2% of non-ATC (9/16), whereas TP53 mutations were found in 76.9% of ATC (10/13) vs. 12.5% of non-ATC (2/16). ATC has a significantly higher prevalence of TP53 mutations. Conclusion: Advanced thyroid cancer is more likely to have actionable mutations. BRAF mutations in advanced PTC may be more common than those previously reported in standard PTC. Moreover, ATC has a higher rate of TP53 mutation than other thyroid carcinomas. Presentation: Thursday, June 15, 2023

Calcaneus metastasis: a rare presentation of poorly differentiated thyroid cancer.

A 60-year-old woman presented to our clinic with an acute onset 3 months history of right ankle pain. The patient had a history of poorly differentiated thyroid cancer, which was treated with total thyroidectomy, left lateral neck dissection levels II-V and central neck dissection levels VI-VII followed by postoperative I-131 radioactive iodine (131I) ablation therapy 3.7 GBq 6 months ago. The post-131I WBS showed residual iodine-avid thyroid tissue with no other iodine-avid disease or metastasis. SPECT/CT of the neck and chest showed nonavid bilateral pulmonary nodules, discrete nodal masses in mediastinum and nonavid bone lesions. FDG-PET CT scan showed FDG-avid mediastinal lymph nodes (LN), innumerable non-FDG-avid subcentimetric pulmonary nodules and few FDG-avid lytic lesions in the skeleton. X-ray and MRI of the right ankle showed a well-marginated lytic lesion in the posterior body of calcaneus and 5 × 6 cm soft tissue mass lesion, respectively. The histopathology of the calcaneus mass confirmed a positive immunostaining for thyroid origin which includes thyroglobulin and TTF-1 with PAX-8. Endobronchial mediastinal and bronchial LN biopsy confirmed thyroid cancer metastasis. Gene mutation showed HRAS and GNA13 with a high tumor mutational burden. We describe a rare case of poorly differentiated thyroid cancer in a patient who presented with right ankle pain; we confirmed the cause to be a calcaneus metastasis from the thyroid cancer, with calcaneus being an extremely rare site for bone metastases. Gene mutations points toward treatment with immune checkpoint inhibitors. Poorly differentiated thyroid carcinoma (PDTC) usually metastasizes to lung and bone but can rarely occur in the calcaneus. Patients with distant metastases have significantly worse long-term prognosis. Radiotherapy is effective in reducing the metastatic pains as well as reducing the size of the metastasis. PAX-8 staining can be used to differentiate thyroid carcinomas from lung adenocarcinomas. The importance of searching for gene mutations to decide the treatment of PDTC.

Revisiting the cytomorphological features of poorly differentiated thyroid carcinoma: a comparative analysis with indeterminate thyroid fine-needle aspiration samples.

Poorly differentiated thyroid carcinoma (PDTC) is an uncommon high-grade carcinoma of follicular cell origin that is usually overlooked on preoperative fine-needle aspiration (FNA) due to its rarity and cytomorphological overlap with follicular-patterned neoplasms. Definitive diagnosis of PDTC usually requires histologic examination of the resected thyroid tumor. Herein, we describe the cytological and architectural findings of histologically confirmed PDTC cases. A search for all thyroid FNAs with a corresponding surgical diagnosis of PDTC was performed. Surgical diagnoses were reviewed and confirmed using the Turin criteria. In addition, the control group consisted of indeterminate thyroid nodules (FLUS [follicular lesion of undetermined significance] and FN [follicular neoplasm]) that were either benign or well-differentiated thyroid tumors on resection. The PDTC and control groups were both subjected to cytological assessment using specific cytological and architectural parameters, which included cellularity, growth pattern, mitoses, necrosis, chromatin change, discohesion, and anisonucleosis. A total of 36 thyroid FNAs were included in the study. This consisted of 12 histologically confirmed PDTC FNAs and 24 indeterminate thyroid FNAs (FLUS and FN, 12 each). The most frequent findings among PDTC groups were hypercellularity (75%), trabecular/insular growth pattern (58%), branching capillaries (67%), and cellular discohesion (92%). Necrosis (25%), ≥3 mitoses (50%), and anisonucleaosis (42%) were less frequently observed. A peculiar finding was the presence of adenoid cystic carcinoma-like globules in 50% of PDTC cases. Certain findings such as colloid, necrosis, mitoses, and cellular discohesion were helpful in differentiating the two groups. Thyroid fine-needle aspiration remains an essential diagnostic/triage tool for most thyroid nodules/tumors. PDTC can be diagnosed or at least suspected preoperatively based on the demonstration of certain architectural and cytological alterations. Although mitoses and necroses are not always readily identified, an elevated Ki-67 labeling expression could provide additional clues to the diagnosis in some cases.

TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis.

TERT reactivation occurs frequently in human malignancies, especially advanced cancers. However, in vivo functions of TERT reactivation in cancer progression and the underlying mechanism are not fully understood. In this study, we expressed TERT and/or active BRAF (BRAF V600E) specifically in mouse thyroid epithelium. While BRAF V600E alone induced papillary thyroid cancer (PTC), coexpression of BRAF V600E and TERT resulted in poorly differentiated thyroid carcinoma (PDTC). Spatial transcriptome analysis revealed that tumors from mice coexpressing BRAF V600E and TERT were highly heterogeneous, and cell dedifferentiation was positively correlated with ribosomal biogenesis. Mechanistically, TERT boosted ribosomal RNA (rRNA) expression and protein synthesis by interacting with multiple proteins involved in ribosomal biogenesis. Furthermore, we found that CX-5461, an rRNA transcription inhibitor, effectively blocked proliferation and induced redifferentiation of thyroid cancer. Thus, TERT promotes thyroid cancer progression by inducing cancer cell dedifferentiation, and ribosome inhibition represents a potential strategy to treat TERT-reactivated cancers.

Incidence and Clinicopathological Features of Differentiated High-Grade Thyroid Carcinomas: An Institutional Experience.

Differentiated high-grade thyroid carcinoma (DHGTC) is a new entity in the 2022 WHO classification. We aimed to investigate the incidence and clinicopathological features of differentiated HG thyroid carcinoma (DHGTC) and compare the clinicopathological parameters of DHGTC, DTC without HG features, and poorly differentiated thyroid carcinoma (PDTC). A total of 1069 DTCs including papillary thyroid carcinomas (PTCs) and follicular thyroid carcinomas (FTCs) were included in this study. Consecutive 22 PDTCs were also included for comparative purposes. There were a total of 14 (1.3%) cases of DHGTCs, with 13 HGPTCs (1.2% of PTCs) and one HGFTC (6.7% of FTCs). Compared to DTCs without HG features, DHGTCs were associated with larger tumor size, presence of blood vessel invasion, gross extrathyroidal extension, distant metastasis at the time of diagnosis, higher American Joint Committee on Cancer stage, high American Thyroid Association risk, and TERT promoter mutations. DHGTC and PDTC showed a significantly shorter recurrence-free survival (RFS) than DTC without HG features. Multivariate Cox regression analysis revealed that blood vessel invasion, lateral node metastasis, TERT promoter mutations, and HG features were independent prognostic factors (all p < 0.05). When tumor necrosis and increased mitotic count were evaluated separately, tumor necrosis, but not increased mitotic counts, was found to be an independent prognostic factor (p = 0.006). This study confirmed that DHGTC is significantly associated with aggressive clinicopathological features and poor clinical outcomes, similar to PDTC. Although the incidence is low, careful microscopic examination of HG features in DTC is required.

Cytological and Ultrasound Features of Thyroid Nodules Correlate With Histotypes and Variants of Thyroid Carcinoma.

Prognosis is excellent for papillary thyroid carcinoma (PTC), noninvasive follicular thyroid neoplasia with papillary-like nuclear features (NIFT-P), and follicular thyroid carcinoma (FTC) but is poor for poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Among PTCs, the prognosis is more favorable for follicular (FV-PTC) and classic (CV-PTC) than for tall cell (TCV-PTC), and solid (SV-PTC) variants. To associate histotypes and variants of thyroid carcinoma with ultrasound and cytological features. Histology of 1018 benign tumors and 514 PTC (249 CV, 167 FV, 49 TC, 34 SV, and 15 other variants), 52 NIFT-P, 50 FTC, 11 PDTC, and 3 ATC was correlated with fine-needle aspiration biopsy categories (Italian classification: TIR1, TIR2, TIR3A, TIR3B, TIR4, and TIR5) and ultrasound features at the Endocrinology Unit, University Hospital of Pisa. In total, 1117 patients with thyroid nodule(s) who underwent thyroidectomy were included. Of PTC, 36.3% had indeterminate cytology (TIR3A or TIR3B), 56.6% were suspicious for malignancy or malignant (TIR4 or TIR5); 84.0% FTC and 69.3% NIFT-P were TIR3A or TIR3B; 72.5% FV-PTC and 73.6% SV-PTC were TIR3A or TIR3B; 79.9% CV-PTC and 95.9% TCV-PTC were TIR4 or TIR5. The association of a hypoechoic pattern, irregular margins, and no microcalcifications was more frequent in TCV-PTC than in CV-PTC (P = .02, positive predictive value = 38.9%; negative predictive value = 85.5%). At cytology, most FTC, NIFT-P, FV-PTC, and SV-PTC were indeterminate, most CV-PTC and TCV-PTC were suspicious for malignancy or malignant. Ultrasound can be helpful in ruling out TCV-PTC.

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.

Characteristics of PTEN Mutation in Thyroid Tumours: A Retrospective Chart Review

While some studies suggest that PTEN mutations correlate with a low-risk phenotype in pediatric thyroid nodules, the relationship between the mutation and malignancy in the adult populations is abstruse. This study investigated whether PTEN mutations result in thyroid malignancy, and whether these malignancies are aggressive. This multicenter study involved 316 patients who underwent preoperative molecular testing, and subsequent lobectomy or total thyroidectomy at two quaternary care hospitals. A four-year retrospective review was performed on the 16 charts of patients that opted for surgery following a positive PTEN mutation on molecular testing results from January 2018 to December 2021. Of the total 16 patients, 37.5% (n = 6) had malignant tumours, 18.75% (n = 3) had non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), and 43.75% (n = 7) had benign disease. Aggressive features were detected in 33.33% of the malignant tumours. Malignant tumours were found to have a statistically significant higher allele frequency (AF). The aggressive nodules were all poorly differentiated thyroid carcinomas (PDTCs) with copy number alterations (CNAs) and the highest AFs.

Outcomes of lenvatinib therapy in poorly differentiated thyroid carcinoma.

Lenvatinib showed promising results in a subgroup of patients with poorly differentiated thyroid carcinoma (PDTC) in the SELECT trial. Our aim was to report the effectiveness and tolerability of lenvatinib in our series of PDTC patients. Medical records of eight consecutive patients with PDTC treated with lenvatinib in a single center between January 2019 and October 2022 were retrospectively reviewed. Inclusion criteria were PDTC diagnosis based on Turin criteria and evidence of disease progression in the previous 6 months. Eight PDTC patients received an average dose of lenvatinib of 18.1 mg for a median duration of treatment of 10.3 months. The baseline Eastern Cooperative Oncology Group performance status was ≥2 in 50% of patients. Two patients had unresectable primary tumor. Seven patients showed extrathyroidal disease, particularly mediastinal lymph nodes (85.7%), lung (71.4%), and bone (71.4%). The disease control rate was 100%, with partial response and stable disease in 12.5 and 87.5%, respectively. The median time to best overall response was 3 months, and the median duration of response was 7.5 months. Median progression-free survival was 12 months and median overall survival was not reached. At 6, 12, and 18 months, overall survival was 87.5, 71.4, and 57.1%, respectively. All patients experienced drug-related adverse effects (AEs). Four (50%) had dose reductions and two (25%) had temporary treatment interruptions. Lenvatinib was stopped in two patients due to grade ≥3 AEs. Lenvatinib is an effective treatment for real-world PDTC patients. Adequate management of comorbidities and AEs increases treatment tolerability and minimizes dose reductions.

High-Grade Non-Anaplastic Thyroid Carcinomas of Follicular Cell Origin: A Review of Poorly Differentiated and High-Grade Differentiated Carcinomas.

Poorly differentiated thyroid carcinoma (PDTC) and high-grade differentiated thyroid carcinoma (HGDTC) are considered high-grade follicular-derived thyroid carcinomas, with prognoses intermediate between well-differentiated and anaplastic thyroid carcinoma. Both share the presence of invasion, thyroid follicular-cell origin, and tumor necrosis or increased mitoses (≥ 3 mitoses per 2 mm2 in PDTC and ≥ 5 mitoses per 2 mm2 in HGDTC), without anaplastic dedifferentiation. PDTC must possess solid, trabecular, or insular growth and lack classic papillary-like nuclei; HGDTC can be of any architectural or nuclear morphology (follicular-like, papillary-like, oncocytic). Transformation may be accompanied by acquisition of high-risk mutations (such as TP53 or TERT promoter) on top of RAS-like or BRAF p.V600E-like (including NTRK-fusion) initial driver mutations. These carcinomas most frequently affect adults and often present with metastases (20-50%) or wide local invasion. As PDTC and HGDTC may be radioactive iodine resistant, post-surgical therapy may consist of external beam radiotherapy or targeted, mutation-dependent chemotherapy, such as tyrosine kinase inhibitors. Ten-year disease specific survival is as low as 50%. Awareness of high-grade features in the diagnostic setting is important for patient prognosis and triage of tissue for molecular analysis in order to guide relevant clinical management and therapy.

PD-L1 expression in rare and aggressive thyroid cancers: A preliminary investigation for a role of immunotherapy.

Programmed cell death ligand-1 (PD-L1) immunoexpression status determines the response to immunotherapy in many cancers. Limited data exist on PD-L1 status in aggressive thyroid tumors. We investigated PD-L1 expression across thyroid cancers and correlated it with their molecular profile. Sixty-five cases of differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) were assessed for PD-L1 expression (clone SP263, VENTANA). The differentiated cases encompassed the aggressive hobnail and tall cell subtypes of papillary thyroid carcinoma (PTC) besides classical PTC and follicular thyroid carcinoma (FTC). Ten nodular goiters (NG) were also evaluated. Tumor proportion score (TPS) and H-score were calculated. BRAFV600E and H-/K-/N-RAS were assessed using allele-specific real-time polymerase chain reaction (PCR). Fisher's exact and Kruskal-Wallis tests were used to investigate the associations between the categorical variables and compare PD-L1 scores with the mutation status. Most PTC (87%) and ATC (73%) cases were PD-L1 positive (TPS ≥1%), with significantly higher positivity rates than NG (20%). TPS >50% was seen in 60% ATC and 7% PTC cases. The median TPS and H-score of ATC were 56 (0-96.6) and 168 (0-275), respectively, and of PTC were 9.6 (4-16.8) and 17.8 (6.6-38.6), respectively. The scores were similar across the PTC subtypes. Only one case each of FTC and PDTC was PD-L1 positive. PD-L1 expression correlated significantly with BRAFV600E, but not with RAS mutation. ATC showed intense and diffuse PD-L1 staining. Although most PTCs were PD-L1 positive, the expression was weaker and patchy, irrespective of the histological subtype. Results of this pilot study indicate that ATC is most likely to respond to immunotherapy. PTC, FTC, and PDTC may be less amenable to immunotherapy. PD-L1 expression correlated significantly with BRAFV600E, allowing for combined targeted therapy.