Aggressive Variants Of Papillary Thyroid Carcinoma Research Articles

Prediction of the Aggressive Clinical Course of Papillary Thyroid Carcinoma Based on Fine Needle Aspiration Biopsy Molecular Testing.

Molecular genetic events are among the numerous factors affecting the clinical course of papillary thyroid carcinoma (PTC). Recent studies have demonstrated that aberrant expression of miRNA, as well as different thyroid-related genes, correlate with the aggressive clinical course of PTC and unfavorable treatment outcomes, which opens up new avenues for using them in the personalization of the treatment strategy for patients with PTC. In the present work, our goal was to assess the applicability of molecular markers in the preoperative diagnosis of aggressive variants of papillary thyroid cancer. The molecular genetic profile (expression levels of 34 different markers and BRAF mutations) was studied for 108 cytology specimens collected by fine-needle aspiration biopsy in patients with PTC having different clinical manifestations. Statistically significant differences with adjustment for multiple comparisons (p < 0.0015) for clinically aggressive variants of PTC were obtained for four markers: miRNA-146b, miRNA-221, fibronectin 1 (FN1), and cyclin-dependent kinase inhibitor 2A (CDKN2A) genes. A weak statistical correlation (0.0015 < p < 0.05) was observed for miRNA-31, -375, -551b, -148b, -125b, mtDNA, CITED1, TPO, HMGA2, CLU, NIS, SERPINA1, TFF3, and TMPRSS4. The recurrence risk of papillary thyroid carcinoma can be preoperatively predicted using miRNA-221, FN1, and CDKN2A genes.

Hirurško lečenje solidne varijante papilarnog karcinoma štitaste žlezde - petnaestogodišnje iskustvo tercijarnog centra

Aim: Papillary thyroid carcinoma (PTC) is a well differentiated, highly curable cancer, with a wide variety of histological forms. Although most of these variants are indolent, aggressive variants of PTC have been described. These variants include tall cell variant (TCV), hobnail variant (HV), columnar cell variant (CCV), diffuse sclerosing variant (DSV) and solid variant (SV). Solid variant represents one of the rarest forms of papillary thyroid carcinoma, with an incidence of about 2.6% according to retrospective studies. Methods: In this retrospective study, data of all patients that underwent thyroid surgery in our Clinic between January 2008 and January 2018 were analyzed. All relevant information was obtained from a prospectively maintained institutional database. Results: Of total of 1867 consecutive patients operated for follicular derived thyroid carcinomas during ten-year period, 38 had solid variant PTC as a definitive pathohistological finding (14 male and 24 female). The incidence of solid variant PTC is 2.04% in our series. Patient follow-up ranged from 36 to 168 months, disease specific five-year survival rate was 97.4%. Conclusion: Considering the scarcity of research discussing the prognosis of this variant of PTC, we believe that the treatment plan should be decided based on the extent of tumor and the experience of clinicians. WHO classification of thyroid neoplasms from 2022,may shed some light as to why the prognosis of solid variant PTC may be less aggressive than previously thought.

Does Locally Advanced Thyroid Cancer Have Different Features? Results from a Single Academic Center.

Background: Despite the fact that the majority of thyroid cancers are indolent, 15% of patients with well-differentiated carcinoma including papillary thyroid carcinoma (PTC) present with locally advanced thyroid cancer (LATC) at diagnosis. The current study analyzes a cohort of patients with LATC focusing on their risk for local recurrence, distant metastases, and overall survival. Materials and methods: From January 2010 to December 2020, 65 patients with LATC were retrieved, including 42 cases with preoperative cytological samples. BRAFV600E and TERT mutations were performed on both cytology and histopathology specimens in this cohort. Results: Among the 65 cases, 42 (65%) were women. The median age was 60.1 years. Histological diagnoses included 25 (38.4%) with classic PTC and 30 (46.1%) aggressive variants of PTC, mostly tall cell variant (17 cases, 26.1%). Multifocality was seen in 33 cases (50.8%). All patients had nodal metastases. The most common site of extrathyroidal extension was the recurrent laryngeal nerve (69.2%). Staging revealed 21 cases were stage I, none were stage II, 33 were stage III, and 7 were stage IVa and 4 stage IVb. No differences were found between well and poorly/undifferentiated thyroid cancers. Conclusion: These data suggest that locally advanced thyroid cancers, including variants of PTC, exhibit a more aggressive biological course and should accordingly be more assertively managed.

Comparison of the clinicopathological features and oncologic outcomes of the classic papillary thyroid carcinoma with tall cell features and tall cell variant.

The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) (TCVPTC) is the most common aggressive variant of PTC. Classic PTC with tall cell features (TCF) is defined as PTC with noticeable tall cells but the percentage of these cells is lower than that required for the diagnosis of TCVPTC. We aimed to investigate the potential differences between TCVPTC and classic PTC with TCF with respect to clinicopathological characteristics and oncologic outcomes. We retrospectively assessed 509 patients with TCVPTC or classic PTC with TCF who underwent thyroid surgery between January 2013 and December 2018 at the Seoul St. Mary's Hospital (Seoul, Korea). Clinicopathological characteristics and oncologic outcomes between TCVPTC and classic PTC with TCF were compared in terms of disease-free survival (DFS). The mean follow-up duration was 70.7±21.7 months. The mean tumor size was significantly larger in the TCVPTC group. There was no significant difference between the TCVPTC and classic PTC with TCF groups with respect to DFS. Tumor size >2 cm [odds ratio (OR), 1.922; P=0.019], bilaterality (OR, 1.668; P=0.030), extrathyroidal extension (ETE) (OR, 2.352; P=0.002), and lateral LN metastasis (OR, 1.700; P=0.045) were significantly associated with TCVPTC compared with classic PTC with TCF. TCVPTC and classic PTC with TCF have similar clinicopathological characteristics and oncologic outcomes. Therefore, we suggest a potential re-classification of classic PTC with TCF from low-risk to intermediate-risk category in the American Thyroid Association (ATA) risk stratification system.

Diffuse intrathyroidal dissemination of papillary thyroid carcinoma with no stromal fibrosis at presentation: A pattern of aggressive differentiated thyroid carcinoma

BackgroundMultifocal Papillary thyroid carcinoma (PTC) is a very common condition. In certain cases, it is possible to find tens to hundreds of foci with a diffuse intrathyroidal spread in the whole thyroid with no stromal fibrosis. Herein, PTC with such features was nominated as diffuse disseminate variant (DDV) PTC. The aim of the present study was to investigate the histopathological characteristics, molecular features, and biological behavior of DDV and compare the characteristics of DDV to diffuse sclerosing variant (DSV) PTC. Materials and methodsThirty-four DDV and 23 DSV cases were identified from consecutive surgical specimens diagnosed with PTC between 2014 and 2019. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of DDV and DSV. ResultsDDV was commonly diagnosed in young patients and exhibited high rates of LNM (100 %), ETE (61.8 %), and LVI (44.1 %); however, they did not differ from DSV (P > 0.05). Male patients were more frequently diagnosed with DDV than with DSV (P < 0.001). The size of the largest tumor was significantly greater in DDV than in DSV patients (P = 0.008). In addition, BRAFV600E mutation was significantly higher in the DDV than in the DSV group (P < 0.001). The RET/PTC rearrangement was more frequent in DSV than in DDV patients; however, the difference was not statistically significant (P = 0.106). Moreover, DDV had a higher rate of recurrence compared to DSV treated with the same protocol (total thyroidectomy followed by radioactive iodine (RAI) treatment) (47.1 % and 8.7 %, P = 0.002). ConclusionsDDV should be regarded as a novel aggressive variant of PTC with distinct clinicopathological characteristics, aggressive biological behaviors, and a high recurrence.

Genetic Profiles of Aggressive Variants of Papillary Thyroid Carcinomas.

Simple SummaryAggressive variants of papillary thyroid carcinoma (PTC) are associated with unfavorable clinical outcomes. However, limited data exist on the genetic profile of these variants of PTC. We performed targeted next-generation sequencing in 36 tissue samples from patients with aggressive variants of PTC. Aggressive variants of PTC had a higher prevalence of the BRAF mutation and a lower prevalence of RAS mutation than other types of thyroid cancer. The prevalence of mutations in the TERT promoter, TP53, and genes encoding histone methyl transferases (HMTs), switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, and the phosphoinositide 3-kinase/protein kinase B (PKB/AKT)/mammalian target of the rapamycin (PI3K/AKT/mTOR) pathway was between the range of PTCs and poorly differentiated/anaplastic carcinoma from The Cancer Genome Atlas (TCGA) and the Memorial Sloan Kettering Cancer Center (MSKCC) data.Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

Hobnail variant of papillary thyroid carcinoma showing goiter-like presentation and rapid growth.

SummaryWe present the case of a 47-year-old Caucasian previously healthy woman with a voluminous thyroid nodule occupying almost the entire anterior neck region. The lesion had progressively increased in size during the previous 3 months and the patient presented intermittent symptoms of dysphagia and odynophagia with a slight change in voice. Fine needle aspiration showed papillary carcinoma. Based on imaging and cytological findings, the patient underwent total thyroidectomy. The surgical sample revealed a totally enlarged thyroid gland (weight: 208 g) with the presence of a poly-lobulated lesion centrally located and involving the isthmus and both lobes. Hobnail features were present in more than 30% of the neoplastic cells in agreement with the criteria for this subtype. Psammoma bodies and focal necrosis were also present. The extra-thyroidal extension included strap muscles and peri-esophageal glands. Immunohistochemistry using VE1 antibody for detecting BRAF-V600E mutation resulted positive. The final diagnosis was papillary thyroid carcinoma (PTC) hobnail variant (HVPTC)-pT4a. The HVPTC is a rare entity and, in most cases, appears like a unifocal lesion with a maximum tumor size of 8 cm reported so far. To our knowledge, this represents the largest tumor ever described (14 cm), showing rapid growth and with multinodular goiter-like aspect.Learning pointsHVPTC is an aggressive variant of PTC, usually associated with radioactive iodine refractoriness, and a higher mortality rate compared to classic PTC. However, there is a marked individual variability in this association.HVPTC usually appears as small unifocal lesion but a multinodular goiter presentation may occur.The present case highlights that despite of the histology, our patient achieved a high ablation success rate after radioactive iodine therapy.

Association between preoperative thyrotrophin and clinicopathological and aggressive features of papillary thyroid cancer.

We aimed to investigate the relation between preoperative serum thyrotrophin (TSH) and clinicopathological features in patients with papillary thyroid carcinoma (PTC) and microcarcinoma (PTMC). Patients who underwent thyroidectomy and diagnosed to have benign nodular disease or PTC/PTMC in our clinic were evaluated retrospectively. Patients with a previous history of thyroid surgery, patients using antithyroid medications or thyroid hormone and patients with tumors known to be unresponsive to TSH were excluded. Data of 1632 patients were analyzed. Histopathological diagnosis was benign in 969 (59.4%) and malignant in 663 (40.6%) patients. Preoperative median serum TSH was significantly higher in malignant compared to benign group (1.41 IU/dL vs. 0.98 IU/dL, p < 0.001). Malignancy risk increased gradually as going from hyperthyroidism to euthyroidism and hypothyroidism (20, 40.6, and 59.1%, respectively, p < 0.05). Serum TSH was lowest in benign nodular disease, higher in PTMC and highest in PTC (p < 0.001). This was also true when patients with positive antithyroid peroxidase/antithyroglobulin and with lymphocytic thyroiditis were excluded from the analysis (p < 0.001). Serum TSH was higher in patients with bilateral tumor, capsular invasion and lymph node metastasis (LNM) compared to patients with unilateral tumor, without capsule invasion and without LNM, respectively (p = 0.036, p = 0.002, and p = 0.001, respectively). Patients with aggressive variant PTC had higher serum TSH than nonaggressive ones (p < 0.05). Preoperative serum TSH is associated with PTMC, PTC and LNM. Serum TSH seems to be related with thyroid cancer regardless of autoimmunity. With the present study, for the first time, we showed an association between serum TSH and aggressive variants of PTC.

Hobnail variant of papillary thyroid carcinoma: molecular profiling and comparison to classical papillary thyroid carcinoma, poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma.

BackgroundAs a rare but aggressive papillary thyroid carcinoma (PTC) variant, the genetic changes of hobnail variant of PTC (HVPTC) are still unclear.ResultsThe prevalence of HVPTC was 1.69% (18/1062) of all PTC diagnosed in our cohort. 73 samples from 55 patients (17 HVPTC, 26 CPTC, 7 PDTC and 5 ATC) were successfully analyzed using targeted NGS with an 18-gene panel. Thirty-seven mutation variant types were identified among 11 genes. BRAF V600E mutation was the most common mutation, which is present in almost all HVPTC samples (16/17, 94%), most CPTC samples (20/26, 77%), and none of the ATC and PDTC samples. TERT promoter mutation (C228T) was identified in 2 ATC and one HVPTC patient. RAS and TP53 mutation are almost exclusively present among ATC and PDTC samples although TP53 mutation was also observed in 3 HVPTC patients. Six different GNAS mutations were identified among 8 CPTC patients (31%) and none of the HVPTC patients. The only patient who died of disease progression harbored concomitant TERT C228T mutation, BRAF V600E mutation and TP53 mutation.MethodsHVPTC cases were identified from a group of 1062 consecutive surgical specimens diagnosed as PTC between 2000 and 2010. Targeted next-generation sequencing (NGS) was applied to investigate the mutation spectrum of HVPTC, compared to classical PTC (CPTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC).ConclusionAs an aggressive variant of PTC, HVPTC has relatively specific molecular features, which is somewhat different from both CPTC and ATC/PDTC and may underlie its relatively aggressive behavior.

PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer

Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We reveal that platelet derived growth factor receptor alpha (PDGFRα) specifically drives dedifferentiation in PTC by disrupting the transcriptional activity of thyroid transcription factor-1 (TTF1). PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. TTF1 is required for follicular cell development and disrupting its function abrogates thyroglobulin production and sodium iodide transport. PDGFRα also promotes a more invasive and migratory cell phenotype with a dramatic increase in xenograft tumor formation. In patient tumors we confirm that nuclear TTF1 expression is inversely proportional to PDGFRα levels. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. We demonstrate in SCID xenografts that focused PDGFRα blockade restores iodide transport and decreases tumor burden by >50%. Focused PDGFRα inhibitors, combined with radioactive iodine, represent an additional avenue for treating patients with aggressive variants of PTC.

Tall cell variant of papillary thyroid carcinoma: a population-based study in Iceland.

The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is an aggressive variant of PTC that is believed to have worse outcomes than classical PTC. The objective of this study was to investigate the incidence, survival, and disease recurrence of patients with TCV and compare them with other PTC in a whole population. Information on all thyroid carcinomas diagnosed in Iceland from 1990 to 2009 was obtained from the Icelandic Cancer Registry. PTC diagnosed postmortem was excluded. The date of diagnosis, sex, and age at diagnosis were registered. All histopathology material was re-evaluated, and papillary thyroid tumors classified as either TCV or other types of PTC. Tumors were classified as TCV if >50% of cells were tall (height > twice the width). TNM stage was determined for all the cases. Endpoints were thyroid cancer-specific death and thyroid cancer recurrence. Out of 376 patients diagnosed with PTC in the study period, 49 (13%) were classified as TCV. Patients with TCV were older (66 years vs. 49 years, p<0.001), more often had pT4 tumors (71% vs. 15%, p<0.001), had higher rates of nodal metastasis (51% vs. 22%, p<0.001), and more often distant metastasis (14% vs. 2%, p<0.001). The age-adjusted incidence of TCV for men was 0.5/100,000 [confidence interval (CI) 0.3-0.7] and for women 0.7/100,000 [CI 0.4-1.0] between 1990 and 2009. The five-year disease-specific survival for TCV was 83% [CI 68-91] compared to 98% [CI 96-99] for other PTC respectively (p<0.001). In multivariate analysis, TCV histology was an independent risk factor for recurrence (hazard ratio (HR) 3.18 [CI 1.48-6.84]) but not for disease specific survival (HR 1.86 [CI 0.77-4.73]). TCV comprises 13% of all diagnosed PTC in Iceland with an incidence of 0.5/100,000 for men and 0.7/100,000 for women. Patients diagnosed with TCV have worse five-year disease-specific survival than patients with other PTC. TCV histology is an independent risk factor for disease recurrence but not for disease-specific survival.

Papillary Thyroid Carcinoma with Prominent Hobnail Features Diagnosed Preoperatively by Fine Needle Aspiration and Demonstrating Constitutive Activation of mTOR Signaling Pathway: A Case Report

Papillary Thyroid Carcinoma (PTC) with prominent hobnail features is a recently recognized aggressive variant of PTC. The cytologic features and molecular characterization have not been fully investigated. We present a patient with a preoperative fine needle aspiration diagnosis of PTC with hobnail features that demonstrated constitutive activation of mTOR pathway with evidence of mTORC2 activation on immunohistochemical staining. These findings may be of value for clinical management, targeted therapy, and prognostication.

Higher Incidence of Tall Cell Variant of Papillary Thyroid Carcinoma in Graves' Disease

Patients with Graves' disease (GD) and thyroid nodules have an elevated risk of developing thyroid carcinomas, which is primarily accounted for by well-differentiated tumors. Among these tumors, certain histological variants, such as the diffuse sclerosing and tall cell carcinoma, are characterized by a more aggressive behavior. The aim of this study was to evaluate the incidence, the clinical behavior in relation to histological variants, and the outcome of papillary thyroid carcinoma (PTC) in a cohort of patients with GD who had undergone thyroidectomy. A total of 2188 patients who underwent total thyroidectomy participated in this retrospective, nonrandomized, population-based study at a General Hospital. Of these patients, 181 had GD. The parameters examined included the clinical characteristics of the tumor and the final pathological examination of the thyroid carcinoma. PTC was diagnosed in 570 patients. Among the 61 with PTC GD-positive, 59.0% presented with the pure papillary variant, 19.7% with the follicular variant, 6.6% with the sclerosing variant, and 18.0% with the tall cell variant (TCV) of PTC. Among 509 PTC GD-negative, 80.6% had pure papillary variant, 9.0% follicular variant, 3.7% sclerosing variant, and 6.1% TCV. Patients with tumor size >5 and ≤10 mm demonstrated that lymph node metastasis (p=0.001) and TCV in histological examination (p=0.003) were statistically significantly associated with GD-positive PTC. The incidence of PTC in GD-positive patients is higher than that in GD-negative patients. Aggressive variants of PTC, such as the TCV, were more frequent in nodular micro-PTC. These findings suggest that prompt and meticulous evaluation of nodules in any patient with GD associated with nodular alterations must be considered.

Brain metastases from papillary thyroid carcinomas

Brain metastasis from papillary thyroid carcinoma (PTC) is extremely rare and carries a poor prognosis. We report nine cases (five females and four males) of brain metastasis of PTC. The age of patients ranged from 46 to 87 years old. The patients presented with nonspecific symptoms such as headaches. Brain metastasis was the first clinical presentation in three of nine patients; two of which had the aggressive tall cell variant of PTC. Six patients had prior history of PTC (four classic, one oncocytic variant, and one columnar cell variant) for 2 to 17 years with a median of 12 years. Gross total resection of brain metastasis was achieved for eight of our patients. Eight patients were treated with radioactive iodine. The median follow-up time was 12 months, ranging from 1 month to 4 years. Three patients died of their disease in 6 months, 21 months and 4 years, respectively after their first presentation of brain metastasis. It seems that these rare aggressive variants of PTC, such as tall cell variant, not only have higher propensity to develop brain metastasis, but also more frequently present with brain metastasis as their first clinical presentation than classic PTC. Furthermore, patients with PTC can develop brain metastasis even after many years.

Suspicious Ultrasound Characteristics Predict BRAFV600E-Positive Papillary Thyroid Carcinoma

Current American Thyroid Association (ATA) guidelines recommend routine cervical ultrasound (US) in thyroid nodule evaluation. Specific US characteristics can help diagnose papillary thyroid carcinoma (PTC). The aim of this blinded cohort study was to determine whether these specific US characteristics can also reliably detect the more aggressive variants of PTC that are often associated with the BRAF(V600E) mutation. After Institutional Review Board approval, we identified a cohort of patients from January 2007 to December 2009 with histologic PTC≥1 cm who had cervical US, initial thyroid surgery, and molecular testing for BRAF(V600E) on fine-needle aspiration biopsy or histology. Preoperative US images were evaluated by a single radiologist, who was blinded to BRAF status, for nodule size and the presence or absence of the following suspicious US features: taller-than-wide shape, ill-defined margins, hypoechogenicity, calcifications, noncystic composition, and absent halo. BRAF-positivity was associated with most known suspicious US findings, including taller-than-wide shape (47% vs. 7%, p<0.001), ill-defined margins (42% vs. 9%, p<0.001), hypoechogenicity (83% vs. 36%, p<0.001), micro/macrocalcifications (87% vs. 24%, p<0.001), and absent halo (85% vs. 27%, p<0.001) but was not associated with noncystic composition. When ≥3 suspicious US features were present, BRAF-positivity was predicted with a positive predictive value of 82%. The absence of suspicious US features together with negative BRAF testing predicted PTC without extrathyroidal extension or lymph node metastasis (negative predictive value 88%). With routine preoperative cervical US and molecular testing, a trained radiologist or surgeon can improve the preoperative characterization of PTC, potentially impacting risk stratification and initial surgical management.

Classification of thyroid follicular cell tumors: with special reference to borderline lesions [Review

We propose a new classification of thyroid follicular cell tumors which is correlated with patient's prognosis. It is unique as to two new categories: borderline malignancy between benign and malignant, and moderately differentiated adenocarcinoma (MDA) as a differentiation classification to stratify tumor aggressiveness. As to diagnostic criteria, we recommend invasiveness (capsular and vascular invasion) to separate benign and malignant and it should not be based on presence or absence of papillary thyroid carcinoma (PTC) type nuclear features (PTC-N). Thus borderline malignancy in our new classification includes some of the formerly malignant tumors and they are 1) papillary microcarcinoma, 2) encapsulated conventional PTC (EncPTC), 3) encapsulated follicular variant PTC (EnFVPTC), 4) well differentiated tumor of uncertain malignant potential (WDT-UMP), 5) follicular tumors of uncertain malignant potential (FT-UMP), and 6) capsular invasion only follicular thyroid carcinoma (FTC). Review of the literature revealed that those thyroid tumors have consistently excellent outcome. Well differentiated follicular cell adenocarcinoma (WDA) in our classification includes common type PTC and low-risk follicular carcinoma (FTC). They are invasive (diffuse infiltrative) common type PTC and minimally invasive type FTC with less than 4 foci of angioinvasion. Moderately differentiated follicular cell adenocarcinoma (MDA) includes FTC with angioinvasion (more than 4), aggressive variants of PTC, such as tall cell, columnar cell, solid, loss of cellular polarity/cohesiveness (hobnail) variants and encapsulated carcinoma with high grade histology. Poorly differentiated carcinoma (PDC) includes PDC of WHO definition, insular carcinoma, tumors with minor anaplastic transformation and tumors with distant metastasis at presentation.

Tall-Cell Variant of Papillary Thyroid Carcinoma: A Matched-Pair Analysis of Survival

The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC) is considered a more aggressive variant of PTC, with a poor prognosis. This is largely due to the tendency for TCV to present at an older age and with extrathyroidal extension (ETE). When these two variables are controlled for, it is unclear whether tall-cell histology alone portends a poor prognosis. Because previous studies have been underpowered to adequately answer this question, we hypothesized that TCV may have poorer prognosis than PTC. Our objective was to utilize a large cancer registry to obtain sufficient power to differentiate between outcomes in cases of TCV and PTC. Using the National Cancer Institute's Surveillance, Epidemiology, and End Results database, we identified 278 TCV patients and 2522 classical PTC patients with sufficient information for a detailed matched-pair analysis. Each TCV patient was matched with a PTC patient for age, sex, extent of ETE, regional and distant metastases, surgical and adjuvant therapy, and year of diagnosis. The TCV cohort was then compared against all PTC cases and matched PTC cases. Compared with classical PTC, TCV patients presented at an older age (54.3 years vs. 46.3 years, p < 0.0001) had a higher rate of ETE (53.6% vs. 30.2%, p < 0.0001) and poorer 5-year disease-specific survival (81.9% vs. 97.8%, p < 0.0001). In the matched-pair analysis comparing TCV patients to the matched PTC cohort, 5-year disease-specific survival was poorer in the TCV cohort (81.9% vs. 91.3%, p = 0.049). The number of deaths in the TCV cohort was higher than in the matched PTC cohort (p = 0.043). TCV exhibits poorer survival than classical PTC. When the major prognostic factors for thyroid cancer are controlled for, including age and ETE, tall-cell histology alone remains a significant prognostic factor for disease-specific death.

Clinical Features and Prognostic Factors for Survival in Patients with Poorly Differentiated Thyroid Carcinoma and Comparison to the Patients with the Aggressive Variants of Papillary Thyroid Carcinoma

We performed this study to compare the clinicopathologic features and outcomes between the patients with poorly differentiated thyroid carcinoma (PDTC) and the patients with the aggressive variants of papillary thyroid carcinoma (PTC). To evaluate the prognostic factors for survival of the patients with PDTC, we selected 49 patients with PDTC and 23 patients with the aggressive variants of PTC from three hospitals during the recent 15 years. The five-year survival rate and clinicopathologic features of the patients with PDTC were not different from those of the patients with the aggressive variants of PTC. Univariate analysis revealed the significant poor prognostic factors for survival of the patients with PDTC and the aggressive variants of PTC as follows: 1) an age more than 45 years, 2) a tumor size larger than 4 cm, 3) the presence of tumor invasion to extrathyroidal tissue or the trachea, 4) the presence of cervical lymph node invasion, 5) the presence of distant metastasis, 6) the absence of high-dose radioactive iodine (RAI) therapy, and 7) TNM stage II, III and IV. Distant metastasis and high-dose RAI therapy were independent significant predictors for survival of the patients with PDTC and the aggressive variants of PTC on multivariate analysis. However, distant metastasis was the only independent significant predictors for survival of the patients with PDTC excluding patients with the aggressive variants of PTC.

Cytologic Grading of Aggressive and Nonaggressive Variants of Papillary Thyroid Carcinoma

To distinguish preoperatively between the usual nonaggressive (classic, follicular, and mixed-papillary and follicular variants) and the aggressive (tall-cell, columnar-cell, and sclerosing diffuse) variants of papillary thyroid carcinoma (PTC), the fine-needle aspiration cytologic smears of 30 cases of PTC were retrospectively reviewed. A three-class grading system, based on the evaluation of four cytologic parameters (cell size, number of nuclear pseudoinclusions, nuclear pleomorphism, and type of chromatin), was applied to each case. A statistically significant association between the cytologic classes and the histologic features of the cases was found. All cytologic grade 1 cases corresponded to the nonaggressive histologic variants, whereas all cytologic grade 3 cases showed features of the aggressive variants of PTC at histologic level.