Five-Year Follow-Up of Health-Related Quality of Life in Differentiated Thyroid Cancer Patients Treated with Total Thyroidectomy and Radioiodine in Sweden: A Nationwide Prospective Cohort Study.

Background: Despite a good prognosis, survivors of differentiated thyroid cancer (DTC) may have reduced health-related quality of life (HRQOL) many years after treatment, and it is unclear how suppression of thyroid-stimulating hormone (TSH) may contribute to HRQOL. This study investigated changes in HRQOL in the 5 years following DTC treatment, the association between HRQOL and TSH suppression, and how HRQOL compares to the general population. Methods: In this nationwide prospective cohort study, 487 patients with DTC were identified between 2012 and 2017 from all Swedish hospitals treating patients with DTC. Patients treated with total thyroidectomy and planned for radioiodine answered the Swedish version of the Short Form-36 Health Survey (SF-36) and a study specific questionnaire at treatment and after 1, 3, and 5 years. Summary measures for physical and mental QOL were derived from the SF-36, and TSH values were collected from patient records. To study changes in HRQOL over time, linear mixed models were fitted on multiply imputed data, with all patients and measurement points included in the model. Results: In total, 351 patients consented to participate in the study. In the 5 years following DTC treatment, physical QOL did not change significantly with time, while mental QOL improved by on average 0.61 (p < 0.001) per year. TSH levels were not predictive of either physical or mental QOL, or their change over time. At 5 years, there was a significant difference in physical and mental QOL compared with the Swedish general population, but effect sizes were small (Cohen's d = 0.29 and -0.21, respectively). The SF-36 domains general health, vitality, social functioning, and mental health were lower at 5 years compared with the general population (difference 8.7-13.3), and these differences were clinically significant. Conclusions: The mental component of HRQOL improves over time following DTC treatment. HRQOL in patients with DTC is not explained by TSH suppression. Although overall differences in physical and mental HRQOL compared with the general population were small 5 years after treatment, several specific psychosocial HRQOL domains were clinically meaningfully reduced. Psychosocial health issues should be screened for during DTC follow-up.

Iodine avidity in papillary and poorly differentiated thyroid cancer is predicted by immunohistochemical and molecular work-up.

Background: Successful radioiodine treatment of differentiated thyroid cancer requires iodine avidity: that is, the concentration and retention of iodine in cancer tissue. Several parameters have previously been linked with lower iodine avidity. However, a comprehensive analysis of which factors best predict iodine avidity status, and the magnitude of their impact, is lacking. Methods: Quantitative measurements of iodine avidity in surgical specimens (primary tumour and lymph node metastases) of 28 patients were compared to immunohistochemical expression of the thyroid-stimulating hormone receptor, thyroid peroxidase (TPO), pendrin, sodium-iodide symporter (NIS) and mutational status of BRAF and the TERT promoter. Regression analysis was used to identify independent predictors of poor iodine avidity. Results: Mutations in BRAF and the TERT promoter were significantly associated with lower iodine avidity for lymph node metastases (18-fold and 10-fold, respectively). Membranous NIS localisation was found only in two cases but was significantly associated with high iodine avidity. TPO expression was significantly correlated with iodine avidity (r = 0.44). The multivariable modelling showed that tumour tissue localisation (primary tumour or lymph node metastasis), histological subtype, TPO and NIS expression and TERT promoter mutation were each independent predictors of iodine avidity that could explain 68% of the observed variation of iodine avidity. Conclusions: A model based on histological subtype, TPO and NIS expression and TERT promoter mutation, all evaluated on initial surgical material, can predict iodine avidity in thyroid cancer tissue ahead of treatment. This could inform early adaptation with respect to expected treatment effect.

Thyroglobulin expression, Ki-67 index, and lymph node ratio in the prognostic assessment of papillary thyroid cancer.

The clinical significance of thyroglobulin (Tg) expression in papillary thyroid cancer (PTC) has not been systematically explored in relation to the Ki-67 index, lymph node ratio (LNR), or other conventional prognostic predictors. In this retrospective study of 327 patients with PTC, we investigated the immunohistochemical expression of Tg in both primary tumors and their matching lymph node metastases in relation to the Ki-67 index, LNR, and clinical data. Tumoral Tg immunoreactivity was inversely correlated to the Ki-67 index and tumor recurrence. The Ki-67 index was higher in lymph node metastases (mean 4%) than in the primary tumors (mean 3%). Reduced Tg expression, estimated as 0-25% Tg positive tumor cells, was more common in lymph node metastases compared to primary tumors. In addition to advanced metastatic burden (defined as N1b stage and LNR ≥ 21%), low Tg expression (0-25% positive tumor cells) in lymph node metastases had a significant prognostic impact with shorter recurrence-free survival. These findings support the potential value of histopathological assessment of Tg expression and Ki-67 index in lymph node metastases as complementary predictors to anticipate the prognosis of PTC patients better.

Dosimetric dependencies on target geometry and size in radioiodine therapy for differentiated thyroid cancer.

Purpose Radioiodine therapy is used in most disease stages for differentiated thyroid cancer. Its success depends on several factors, such as lesion size, completeness of surgery, extent of metastasis and tumoural iodine avidity. We aimed to investigate the importance of non-spherical geometries and size of metastases and thyroid remnants for the absorbed dose delivered. Methods Absorbed doses and energy depositions from homogeneously distributed iodine-131 in clinically relevant geometries and sizes were calculated using Monte Carlo simulations with MCNP6. A total of 162 volumes with different sizes and geometries corresponding to spheres, and prolate or oblate spheroids were simulated. Results Oblate and prolate spheroids had worse radiation coverage compared to spheres for equal masses, up to a difference of 38% for the most eccentric oblate spheroids and smallest masses simulated (a micrometastasis of mass 0.005 g). The differences in coverage could be explained by different volume - to - surface - area ratios of the spheroids. The impact of size alone caused up to 71% lower absorbed doses per decay in a spherical target mass of 0.005 g compared to 50 g. Conclusions While the iodine avidity, and therefore the total amount of decays, is the predominant contributing factor to absorbed dose in radioiodine therapy, eccentric spheroids and small target sizes can receive substantially lower absorbed doses from the same administration of radioiodine.

Health Anxiety and Its Relationship to Thyroid-Hormone-Suppression Therapy in Patients with Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) has a good prognosis; however, patients often need lifelong follow up, and they face potential side effects. The aim of this study was to investigate health anxiety among DTC patients and its relationship to TSH suppression. In 2020, patients from a previous cohort who were from Stockholm completed the 14-item Short Health Anxiety Inventory (SHAI-14; 0−42; 18 being the threshold for clinical significance) and a study-specific questionnaire. Clinical information was also retrieved from medical records. Linear regression was used to investigate the relationship between the TSH levels and the SHAI-14, while adjusting for potential confounders. In total, 146 (73%) patients were included. A total of 24 respondents (16%) scored 18 or more on the SHAI-14, and the mean score was 11.3. Patients with TSH levels of 0.1−0.5 (mE/L) scored, on average, 3.28 points more (p-value 0.01) on the SHAI-14 compared to patients with TSH levels > 0.5. There was no statistically significant difference between patients with TSH levels < 0.1 and TSH levels > 0.5. Thus, we found no linear relationship between the TSH values and health anxiety. Clinically significant levels of health anxiety are slightly higher than those in the general population, but do not appear to be a major psychiatric comorbidity among patients with DTC.

Development of metastatic poorly differentiated thyroid cancer from a sub-centimeter papillary thyroid carcinoma in a young patient with a germline MET mutation - association or random chance?

BACKGROUND: Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed. CASE PRESENTATION: A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion. CONCLUSIONS: The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.

Pre-Therapeutic Measurements of Iodine Avidity in Papillary and Poorly Differentiated Thyroid Cancer Reveal Associations with Thyroglobulin Expression, Histological Variants and Ki-67 Index.

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy.

The Clinical Significance of Lymph Node Ratio and Ki-67 Expression in Papillary Thyroid Cancer.

BACKGROUND: The N stage in papillary thyroid cancer (PTC) is an important prognostic factor based on anatomical localization of cervical lymph nodes (LNs) only and not the extent of lymphatic metastasis. In this retrospective study, the clinical significance of lymph node ratio (LNR) and tumor cell proliferation in relation to the conventional classification of PTC was explored. METHODS: Patients diagnosed with PTC at the Karolinska University Hospital in Stockholm, Sweden, during the years 2009-2011 were included. The LNR, defined as the number of metastatic LNs divided by the total number of LNs investigated, and the Ki-67 index were analyzed in relation to clinical data. RESULTS: The median number of LN removed was 16 with the following N stage distribution: N0 (26%), N1a (45%), and N1b (29%). A Ki-67 index of ≥3% was significantly correlated with the presence of metastases and tumor recurrence with a sensitivity of 50% and specificity of 80% (p = 0.015). Lymph node ratio ≥21% was related to tumor recurrence with sensitivity of 89% and specificity of 70% (p = 0.006). Patients with LN metastases in the lateral cervical compartment only had significantly lower LNR (14.5%) compared to those with both central and lateral cervical metastases (39.5%) (p = 0.004) and exhibited no tumor recurrence. Increased Ki-67 index was significantly related to LNR ≥21% (p = 0.023) but was not associated with N stage. CONCLUSIONS: The Ki-67 proliferation index and LNR may better reflect the malignant behavior of PTC compared to the anatomical classification of LN metastases solely.

Metastatic-prone telomerase reverse transcriptase (TERT) promoter and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated tall cell variant of papillary thyroid carcinoma arising in ectopic thyroid tissue: A case report.

RATIONALE: Mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF) oncogene and telomerase reverse transcriptase (TERT) promoter region are indicators of poor prognosis in papillary thyroid carcinoma (PTC) and might predict future occurrences of distant metastases. However, the clinical significance of these genetic aberrancies in PTCs arising in ectopic locations is not well established. PATIENT CONCERNS: We describe a patient with a previous history of radioiodine (RAI)-treated hyperthyroidism and a surgically resected right-sided follicular thyroid adenoma. In 2013, a 6 mm follicular variant papillary thyroid carcinoma was diagnosed following a left-sided thyroid lobectomy. The central compartment displayed 9 tumor-free lymph nodes, and no adjuvant treatment was planned. DIAGNOSES: Three years later, a 26 mm pre-tracheal relapse was noted, however, the excised lesion was consistent with a tall cell variant of papillary thyroid carcinoma (TCV-PTC) arising in ectopic thyroid tissue. RAI treatment was commenced. Four years later, a 5 mm subcutaneous lesion in the anterior neck was surgically removed and diagnosed as metastatic TCV-PTC with a codon 600 BRAF mutation and a C228T TERT promoter mutation. INTERVENTIONS: RAI treatment was re-initiated. Molecular re-examination of the primary follicular variant papillary thyroid carcinoma demonstrated a codon 600 BRAF mutation and a TERT promoter wildtype sequence, while the primary TCV-PTC was positive for mutations in both codon 600 of BRAF as well as the TERT promoter. OUTCOMES: The patient is alive and well without signs of relapse 7 months after the latest round of RAI. LESSONS: We conclude that the occurrence of combined BRAF and TERT promoter mutations in the primary lesion from 2016 was associated to the manifestation of distant metastases 4 years later, strengthening the benefit of mutational screening of these genes in clinical routine for thyroid carcinomas arising in aberrant locations.

Cardiovascular Incidence in 6900 Patients with Differentiated Thyroid Cancer: a Swedish Nationwide Study.

INTRODUCTION: To minimize recurrence risk in differentiated thyroid cancer (DTC), TSH is usually lifelong suppressed with levothyroxine. A common consequence of this treatment is subclinical hyperthyroidism which can induce cardiovascular disease (CV). This study's aim was to compare CV incidence in DTC patients with the general population in Sweden. MATERIALS AND METHODS: All Swedish patients diagnosed with DTC in 1987-2013 were included in the cohort study. Lifelong TSH suppression treatment was assumed to be administered to patients in compliance with prevalent national guidelines. Patients were followed from 1 year after DTC diagnosis until December 31, 2014, death, or migration. The event of interest was hospitalization due to any of the following diseases: atrial fibrillation (AF), cerebrovascular disease, cerebral infarction, ischemic heart disease, ischemic heart attack, and heart failure. Standardized incidence ratios (SIRs) were calculated to compare CV incidence between DTC patients and the general population. RESULTS: The cohort consisted of 6900 patients with DTC. Hospitalization was increased among DTC patients for AF (SIR 1.66, CI 95% 1.41-1.94), and women faced increased hospitalization for cerebrovascular disease (SIR 1.20 CI 95% 1.04-1.38). Regarding the remaining CV diseases, no consistent difference in SIR between the groups was observed. CONCLUSION: Compared to the general population, DTC patients have a higher incidence in AF, and female face a slightly higher incidence in cerebrovascular disease. However, there was no difference in hospitalization for other studied CV diseases between DTC patients and the general population.

The Influence of Preoperative Symptoms on the Death of Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are uncommon tumors with an annual incidence of about 1 per 100,000. Usually, SI-NETs have a slow progression, and patients often present with generalized disease. Many patients do well, and the disease has a relatively favorable 5-year survival rate. Some SI-NETs, however, have a more negative prognosis. This study aimed to establish prognostic factors for death identifiable at primary surgery. METHODS: A nested case-control study investigated 1150 patients from the cohort of all patients with a diagnosis of SI-NETs in Sweden between 1961 and 2001. The study cases consisted of all patients who died of SI-NETs during the study period. Each case was assigned a control subject matched by age at diagnosis and calendar period. Possible prognostic factors [gender, degree of symptoms, indication for surgery, World Health Organization (WHO) stage] were evaluated in uni- and multivariable analyses. RESULTS: The patients with symptomatic disease had an increased risk of dying. The indication for primary surgery influenced survival, showing a more negative prognosis for elective surgery. The WHO stage influenced survival, and stage 4 patients had an almost threefold risk of dying compared with stages 1 to 3b patients. CONCLUSIONS: This study showed that preoperative symptoms are important in prognostication for SI-NETs. Hormonal symptoms generally signify a patient with a more advanced disease stage and a worse prognosis. Including symptomatic disease together with the WHO stage and grade could possibly increase the accuracy of prognostication.

Detailed Lymph Node Sectioning of Papillary Thyroid Carcinoma Specimen Increases the Number of pN1a Patients.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy, frequently presenting with lymph node metastasis at the time of diagnosis. Lymph node staging (N) partly determines treatment, follow-up, and prognosis. Since 2011, our institution has employed a more comprehensive histopathological work-up of lymph nodes in patients with PTC. We sought to retrospectively determine the value of serial lymph node level sectioning in PTCs with negative preoperative lymph node status (pN0) as a method to increase the sensitivity of detecting metastatic disease. We included all patients that underwent thyroidectomy and central neck dissection and subsequent comprehensive lymph node level sectioning due to PTC with an initial pN0 status between the years 2011 and 2015 at our institution. Sixty-seven cases of PTC with a median of 10 metastatic free lymph nodes identified per case were included. After serial lymph node sectioning of the central compartment, 11 cases (16 %) revealed lymph node metastasis, six of which (55 %) presented with a small primary tumor (<20 mm, T1). Of all T1 tumors with initial pN0 status, 18 % (T1a) and 9 % (T1b) reached a pN1 stage after comprehensive lymph node sectioning. Cases with altered lymph node status had a median of 15 identified lymph nodes as compared to ten in cases that remained negative. We conclude that comprehensive lymph node sectioning increased the sensitivity of detecting metastases in PTC and altered the pathological TNM staging (pTNM) for a significant number of patients. Although of limited prognostic significance, the method should be considered as an adjunct tool when assessing lymph node status of PTC as a part of the routine histological work-up to ensure an accurate cancer staging.

Correlation between indeterminate aspiration cytology and final histopathology of thyroid neoplasms.

BACKGROUND: Of all thyroid nodules assessed by fine needle aspiration cytology (FNAC), 10-20% are classified as indeterminate/atypical. Traditionally, this group is considered to primarily represent follicular neoplasia. We hypothesize that papillary carcinoma accounts for a significant proportion of lesions classified as "atypical" on FNAC. METHODS: This retrospective study includes 228 patients who had an atypical FNAC result and who were subsequently found to have a malignancy on histologic examination of the excised thyroid lesion. Patients with papillary microcarcinomas, defined as lesions less than 10-mm diameter, were excluded. The study period was from 1987 to 2005. The patients were divided chronologically into 3 groups (n = 76) for analysis: group 1, December 1987-March 1997; group 2, July 1997-October 2002; and group 3, October 2002-December 2005. RESULTS: Age- and sex-distribution of the 3 groups were not significantly different. Median nodule size of group 3 was significantly smaller. The distributions of histopathology of the 3 time periods were significantly different overall (P = .0325). Prevalence of papillary carcinoma was not statistically significant (33/76 vs 34/76 vs 46/76; P = .0636), but showed a statistical significant trend to increase over time (P = .0349). Prevalence of follicular variant papillary carcinoma was also found to be significantly different between the groups (7/76 vs 12/76 vs 19/76; P = .0320; P = .0349). CONCLUSION: Papillary carcinoma accounted for most histopathologically confirmed cancers that had an atypical cytology. Papillary cancer in this group of patients trended up, probably due to a significant increase in the diagnosis of follicular variant of papillary cancer.

Hyperparathyroidism after irradiation for childhood malignancy.

PURPOSE: To examine the occurrence of hyperparathyroidism in a cohort of patients undergoing combined parathyroid and thyroid surgery after previous head-and-neck irradiation for childhood malignancy. METHODS AND MATERIALS: This is a retrospective cohort study for the years 1996 to 2007. The study group comprised patients undergoing surgery in the University of Sydney Endocrine Surgical Unit who had received previous head-and-neck irradiation in childhood and who were identified as having pathologic thyroid and parathyroid characteristics. RESULTS: A total of 53 patients were identified in whom head-and-neck irradiation for the treatment of childhood malignancy had been documented. In each of the cases, thyroid disease was the primary reason for referral for surgery. Five of these patients (10%) were found to exhibit coexisting hyperparathyroidism. The latency period for hyperparathyroidism was less than 20 years in 4 of the 5 cases. There were four conventional parathyroid adenomas and one parathyroid lipoadenoma. All patients exhibited a significant decrease in postoperative calcium levels after surgery. CONCLUSIONS: To our knowledge, this is the first study to document the significant risk of hyperparathyroidism after radiation exposure for childhood malignancy. The timeframe for development of disease is much shorter than that published for individuals who have undergone irradiation for benign diseases. High doses of therapeutic radiation at a young age make childhood survivors of malignancy at especially high risk for developing hyperparathyroidism.

Are possible risk factors for differentiated thyroid cancer of prognostic importance?

OBJECTIVE: The only established risk factor for differentiated thyroid cancer (DTC) is ionizing radiation. How ionizing radiation and other possible risk factors for DTC influence the prognosis has not extensively been investigated. We studied if factors such as smoking, number of children, previous thyroid disorders, previous radiotherapy toward the neck, family history of thyroid diseases, and malignancies influenced survival for patients with DTC. DESIGN: A nested case-control study was conducted within the cohort of all patients diagnosed with DTC in Sweden between 1958-1987. Cases consisted of patients who died from DTC. One control, matched by age at diagnosis, gender, and calendar period was randomly selected from the risk set for each case. Information of risk factors was collected from the medical records. Associations between these factors and prognosis were assessed using conditional logistic regression. MAIN OUTCOME: Smokers had a borderline significant increased risk of dying from DTC. Previous radiotherapy towards the neck region had no prognostic implication. A family history of DTC influenced prognosis although not significant due to few cases. The remaining risk factors studied did not influence survival. CONCLUSIONS: In conclusion, smokers seemed to have a worsened prognosis compared to nonsmokers and a family history of thyroid cancer had a nonsignificant negative effect on survival.