Index Patient Ngs Analyses
When interrogating DNA from the primary PTC and metastatic PDTC using the Oncomine Solid Tumor Panel, a missense variant in exon 2 of the MET gene was found in both the primary tumor and metastasis. This variant was confirmed as constitutional by Sanger sequencing of germline DNA. No somatic mutational events were noted in any gene interrogated. We thereafter submitted DNA and RNA from both tumors for extended analyses using the Oncomine Childhood Cancer Research Assay, and detected a pathognomonic ETV6-NTRK3 gene fusion in both the primary PTC as well as in the metastatic PDTC. No other cancer-related gene mutations or fusions were noted, including the thyroid cancer related genes BRAF, HRAS, KRAS, NRAS, TERT, TP53 and DICER1.
Cellular Classification Of Thyroid Cancer
In thyroid cancer, cell type is an important determinant of prognosis and treatment. The thyroid has two cell types: follicular cells and parafollicular C cells. The management of thyroid cancer depends on the cell of origin and how well the integrity of the cell type is maintained. The four main types of thyroid cancer are divided into the following two categories for clinical management:
Differentiated thyroid cancers.
Parafollicular C cell thyroid cancers.
Standard Treatment Options For Papillary And Follicular Thyroid Cancer
Localized/regional papillary and follicular thyroid cancer
Surgery is the therapy of choice for all primary lesions. Surgical optionsinclude total thyroidectomy or lobectomy. The choice of procedure isinfluenced mainly by the age of the patient and the size of the nodule. Survival results with the two procedures are similar for early-stage disease, with differences in the ratesof surgical complications and local recurrences.
Standard treatment options for localized/regional papillary and follicular thyroid cancer
Standard treatment options for localized/regional papillary and follicular thyroid cancer include the following:
The objective of surgery is to completely remove the primary tumor, while minimizing treatment-related morbidity, and to guide postoperative treatment with RAI. The goal of RAI is to ablate the remnant thyroid tissue to improve the specificity of thyroglobulin assays, which allows the detection of persistent disease by follow-up whole-body scanning. For patients undergoing RAI, removal of all normal thyroid tissue is an important surgical objective. Additionally, for accurate long-term surveillance, RAI whole-body scanning and measurement of serum thyroglobulin are affected by residual, normal thyroid tissue, and in these situations, near total or total thyroidectomy is required. This approach facilitates follow-up thyroid scanning.
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How Is The Stage Determined
The staging system most often used for thyroid cancer is the AJCC TNM system, which is based on 3 key pieces of information:
- The extent of the tumor : How large is the cancer? Has it grown into nearby structures?
- The spread to nearby lymph nodes : Has the cancer spread to nearby lymph nodes?
- The spread to distant sites : Has the cancer spread to the distant organs such as the lungs or liver?
The systems described below are the most recent AJCC systems effective January 2018 and applies to differentiated, anaplastic and medullary thyroid cancers.
Numbers or letters after T, N, and M provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a persons T, N, and M categories have been determined, this information is combined in a process called stage grouping to assign an overall stage. For more information see Cancer Staging.
The staging system in the table below uses the pathologic stage . It is determined by examining tissue removed during an operation. Sometimes, if surgery is not possible right away or at all, the cancer will be given a clinical stage instead. This is based on the results of a physical exam, biopsy, and imaging tests. The clinical stage will be used to help plan treatment. Sometimes, though, the cancer has spread further than the clinical stage estimates, and might not predict the patients outlook as accurately as a pathologic stage.
Targeted Therapies Against Mapk Pathway
Mitogen-Activated Protein Kinase pathways connect extracellular signals to the network that controls cell proliferation, motility, and cell death. Thyroid cancer often presents genetic alterations that activate the MAPK pathway. These mutations include point mutations in BRAF and RAS or RET/PTC translocations . These mutations have been widely studied as a new therapeutic target in advanced thyroid cancer.
Vemurafenib and dabrafenib are BRAFV600E inhibitors that function as ATP-competitive inhibitors. Vemurafenib has a much higher selectivity for mutated BRAF compared to wild type BRAF . A multicenter, phase I study of vemurafenib, included three patients with BRAFV600E mutated RAI-refractory-metastatic thyroid cancer , treated with different doses of vemurafenib at 240360 mg twice daily, and later increased to 720 mg twice a day. One patient had a partial response with a 31% reduction of the target lesion in the lungs, and the other two patients had stable disease . The progression-free interval for the three patients were 11.4, 11.7, and 13.2 months, and the overall survival was 15, 21, and at least 31.7 months. The adverse events were similar to those were reported in a phase I study of patients with metastatic melanoma.
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Generation Of Constitutive Hotair Overexpression
The sequence of HOTAIR was cloned from the LZRS-HOTAIR plasmid and inserted into the pEGFP-Lv105 vector as the working HOTAIR plasmid. pEGFP-Lv105 empty vector was used as a control. Then, we applied lentiviral packaging kit in HEK293T cells to produce lentiviral particles. The MDA-T41 cells were transduced with HOTAIR plasmid- or empty vector-lentiviral particles in 8 µg/ml hexadimethrine bromide -containing growth medium to generate MDA-T41 HOTAIR-OE cells or Control cells, respectively. Then, cells were revived in normal growth medium for an additional 2428 h with subsequent selection in puromycin-containing growth medium.
Additional File : Figure S1
Comparison of HOTAIR expression among PTCs with different genetic background. Figure S2. Overexpression of HOTAIR in the low HOTAIR-expressed K1 cell enhanced proliferation, colony formation and shifted the cell cycle toward G2/M phase. Figure S3.DLX1 expression presented corresponding changes after HOTAIR modulation and had an endogenously negative correlation with HOTAIR levels in PTC cell lines. Table S1. Top 5 genes presented significantly negative correlation with HOTAIR expression in PTC tissues of TCGA data. Table S2. Used primers sequences. Figure S4. The corresponding changes of protein levels after HOTAIR modulation in MDA-T32 and MDA-T41 cell lines. Protein markers of different cell phases, PTEN and p-AKT/AKT ratio were blotted on Scramble/si-HOTAIR cells Protein markers of different cell phases, PTEN and p-AKT/AKT ratio were blotted on Control/HOTAIR-OE cells DLX1 were blotted on Scramble/si-HOTAIR and Control/HOTAIR-OE cells.
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In Vitro Results Of The Fifth Patient
The fifth patient was affected by PDTC and the overall survival was 174 weeks after his first diagnosis. The patient received once radiotherapy. Afterwards, the patient was treated with sorafenib and then with lenvatinib. Both treatments were interrupted because of severe adverse events. RAI-R was diagnosed. No mutation of BRAF was detected . The treatment with TKIs and panobinostat was applied at the cells derived from his resected tumor after they have been kept proliferating in in vitro culture conditions.
3.5.1. Effects on Cell Viability of the Individual Tumor Cells Caused by Treatment with Sorafenib, Panobinostat and Selumetinib
In the PDTT cells of the fifth patient case, selumetinib caused a reduction of cell viability at 100 µM only. Treatment with sorafenib was able to reduce significantly the cell viability at 1 µM already. In addition, 10 and 100 nM panobinostat showed, once again, the strongest efficacy in cell viability reduction .
Effects of selumetinib, sorafenib and panobinostat on cell viability and RAI-U. Real time cell viability of PDTT cells treated with 1 to 100 µM selumetinib and sorafenib and 1 to 100 nM panobinostat . RAI-U after 24 and 48 h of treatment with 10 µM selumetinib, 10 µM sorafenib and 10 nM panobinostat . Shown are means of experiments performed in triplicates ± SD /SEM .
3.5.2. Radioiodine Up-Take after Treatment with Sorafenib, Panobinostat and Selumetinib
3.5.3. Expression of SLC5A5 , HMGA2 and miRNAs
And Their Variants Including Hurthle Cell Tall Cell And Others
These pages offer information for everyone interested in learning more about papillary and follicular thyroid cancer, as well as their variants, including Hürthle cell, tall cell, and others.
About 9 of every 10 people with thyroid cancer have these types of thyroid cancer. They are called differentiated thyroid cancer.
We invite you to read these pages and to explore the further free support services, information, publications, and educational events that are available for patients, families, friends, and health care professionals.
- Papillary and follicular thyroid cancers are referred to as differentiated thyroid cancer, which means that the cancer cells look and act in some respects like normal thyroid cells.
- Papillary and follicular thyroid cancers account for more than 90% of all thyroid cancers. They tend to grow very slowly.
- Their variants include columnar, diffuse sclerosing, follicular variant of papillary, Hürthlecell, and tall cell. Two other variants are considered to be intermediate between differentiated thyroid cancer and poorly differentiated thyroid cancer. The variants tend to grow and spread more than typical papillary cancer.
- If detected early, most papillary and follicular thyroid cancers can be treated successfully. Their treatment and management are similar and are based on staging and individual risk levels.
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Met Gene Variant Predictions And Cosmic Database Findings
In the Exome Variant Server, the specific MET gene variant was reported in 4 out of 12,214 exomes sequenced, and the minor allele frequency was estimated to 0.03%, well below usual cut-offs for distinction of mutations . Moreover, consulting dbSNP, the variant exhibited a near-identical minor allele frequency of 0.000338=0.03%. Moreover, using the PolyPhen2 in silico prediction software, the described variant had an impact score of 0.999, meaning that is highly probable that the variant exhibited a significant consequence for MET protein function. An additional SIFT analysis yielded similar result, with the variant predicted as damaging . To highlight the uncertain nature of this variant using in silico analyses, we also added data from MutationAssessor, in which the variant was predicted as having a low functional impact . Moreover, the p.Arg359Gln substitution is also reported in the COSMIC database as COSV59264672. The mutation has been reported in two neuroblastomas, one paraganglioma, as well as in single cases of prostatic adenocarcinoma, pancreatic adenocarcinoma and squamous cell carcinoma of the lung.
Follicular Cell Thyroid Cancers
From well differentiated to undifferentiated, the types of thyroid cancer from follicular cells are:
Papillary thyroid cancer: This is typically the least aggressive type of thyroid cancer. It accounts for about 80% of thyroid cancer diagnoses. While papillary thyroid cancer usually occurs in only one lobe of the thyroid gland, it appears in both lobes in 10%-20% of cases. Papillary thyroid cancer is most common in women of childbearing age. Its treatment is successful in most patients.
Follicular thyroid cancer: This accounts for about 10% of thyroid cancers. Though it can be more aggressive than papillary thyroid cancer, follicular thyroid cancer usually grows slowly. Treatment for follicular thyroid cancer is similar to papillary thyroid cancer and is successful for most patients.
Both papillary and follicular thyroid cancer are considered well differentiated cancers. Well differentiated thyroid cancer tends to stay contained within the thyroid gland. When it does spread outside the thyroid, the most common locations of spread, or metastasis, are lymph nodes, lungs, bones and the liver.
HÃ¼rthle cell thyroid cancer: Also called oxyphilic cell carcinoma, HÃ¼rthle cell carcinoma was considered a type of follicular thyroid cancer until recently. Most patients diagnosed with HÃ¼rthle cell carcinoma do well, but the outlook may change based on the extent of disease at the time of diagnosis.
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Case Report: Poorly Differentiated Thyroid Carcinoma In A Young Female Patient
Shane Kaysen1^, Peter Anderson2, Jeffrey Mohlman3
1 Rocky Vista University College of Osteopathic Medicine, Parker , South Valley ENT and Steward Healthcare , Professional Diagnostics Inc. and Steward Healthcare , USA
Background: Poorly differentiated thyroid carcinoma is a rare subtype of thyroid cancer that is often overlooked on differentials for thyroid neoplasms, and its etiology is poorly understood. This report provides an additional clinical and genetic profile to the literature of this rare and often complex entity as well as discusses a multitude of genetic findings seen in PDTC.
This tumor type is rare in this age group and has few studies explaining its etiology. The genetic analysis in this case had a unique genetic profile showing MYC amplification and mutations of undetermined significance without the previously reported finding of a DICER1 mutation.
Keywords: Case report poorly differentiated thyroid carcinoma DICER syndrome Turin criteria MYC amplification
Received: 09 February 2022 Accepted: 07 April 2022 Published: 10 May 2022.
Cytomorphology Of Poorly Differentiated Thyroid Carcinoma
The diagnosis of PDTC rests on histologic evaluation and cannot be made with certainty by FNA. Nevertheless, some general comments can be made. Cytologic preparations are usually highly cellular , with numerous isolated tumor cells as well as clusters of overlapping cells. Microfollicles are often present. In many cases the tumor cells are uniform in size and shape,122 but a greater degree of atypia is seen in some cases . Cytoplasm is poorly defined, and occasional cytoplasmic vacuoles are present. Intranuclear inclusions and nuclear grooves also may be seen.122,124 Colloid is scant.
The possibility of PDTC can be supported by the immunocytochemical proliferation index. The Ki67/MIB1 index in well differentiated carcinomas is usually low , whereas the index in PDTC is in the range of 10% to 30%.59
The differential diagnosis is broad in scope. The presence of intranuclear inclusions and grooves in many of these tumors suggests a papillary thyroid carcinoma, but the prominence of isolated cells is unusual and might suggest PDTC. Nuclear pleomorphism, if present, raises the possibility of an undifferentiated carcinoma. Most notably, PDTC has a striking resemblance to MTC, but microfollicles with colloid support the diagnosis of PDTC. Immunohistochemistry can be useful: PDTCs are thyroglobulin-positive and calcitonin-negative.
LORETTA L.Y. TSE, JOHN K.C. CHAN, in, 2009
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Diagnosis Of Hurtle Cell Thyroid Cancer
Hurtle cell thyroid cancer cannot be diagnosed by fine needle aspiration biopsy . The only way to diagnose cancerous Hurthle cells is by surgically removing the whole tumor.
The following tests may be ordered:
Blood tests help show if your thyroid is functioning normally. Tests commonly ordered check levels of thyroid-stimulating hormone and T3 and T4 hormones. Blood tests are also used to monitor thyroid cancers.
Advanced imaging scans of your neck help your physician see the precise location and extent of the suspected cancer including: Ultrasound scan , Computed tomography and scan Magnetic resonance imaging .
Met Gene Variant Predictions
The Exome Variant Server and the Database of Single Nucleotide Polymorphisms were used in order to verify the minor allele frequency of the index patients MET variant. PolyPhen2 , Sorting Intolerant From Tolerant and MutationAssessor were employed to examine if the variant had an impact on the MET protein function. The roles of this specific variant in the somatic setting were analyzed using the Catalogue of Somatic Mutations in Cancer database .
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Characteristics Of Pdtc Cases Stratified By Tg Group
Patients with undetectable and detectable Tg levels showed no significant age or gender differences . Around two-thirds of all cases were older than 45 years and the female-to-male ratio was also similar in both groups .
Characteristics stratified by Tg group
Pathological tumor characteristics in the 2 groups were only statistically different for surgical margins and nodal status patients with detectable Tg had a lower probability of achieving R0 margins and a higher node status . Nevertheless, these patients showed a trend towards more advanced local disease with a higher pT4 status and more frequent extrathyroid extension . No statistical significant differences between the 2 groups were found regarding the size of primary tumor, vascular invasion, or histological subtype.
Clinical Characteristics Of The Ptc Validation Cohort
The clinical characteristics of the PTC validation cohort are shown in Table . The gender distribution was 4:1 , and the mean age at surgery was 36, , reflecting the selective inclusion of young patients. There were 6 cases exhibiting disease relapses, 3 who had died of disease and 2 who died of other causes. 34 cases were positive for the BRAF V600E mutation , and a single PTC exhibited the C228T TERT promoter mutation .
Table 1 Clinical characteristics of the PTC validation cohort
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Literature Selection And Quality Assessment
Inclusion criteria were as follows: patients undergone thyroid surgery for the first time, the pathologic findings were confirmed as multifocal/unifocal PTC, and studies reported both multifocality and unifocality. Level of confidence was determined according to the Oxford Centre for Evidence-Based Medicine, Levels of Evidence .
Exclusion criteria were as follows: non-English articles insufficient data overlapping reports in multiple publications case report, editorials, letters or meeting abstracts patients with non-neoplastic thyroid disease were included and restricted pathological subtypes or genetic background.
The NewcastleOttawa Scale was used by two investigators according to the Cochrane collaboration. Stars were awarded based on patient selection , comparability and the evaluation of outcomes . In cases of disagreement, another investigator provided assessment.