Total thyroidectomy: reduction in postoperative hypoparathyroidism.

Objective: Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy operations for Graves' disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves' disease. Design: Retrospective cohort study from a single institution. Methods: We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves' disease. Results: We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012-2014 to 6% in 2020-2021. For patients with Graves' disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015-2016 to 2% (1 out of 56) in 2020-2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012-2014 to 10% (10 out of 51) in 2020-2021. Conclusion: Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery. Significance statement: Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoperative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves' disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

Risk-stratification of thyroid nodules examined by 18FDG-PET/CT while ensuring congruity between imaging and histopathological localization.

PURPOSE: The risk of malignancy (ROM) in FDG-avid thyroid incidentalomas varies between studies, which may be contributed by discordance between the anatomical localization depicted on 18FDG-PET/CT and by histopathological examination. The purpose was to ensure anatomical congruity between the index tumour identified by 18FDG-PET/CT and the histopathological examination, in order to assess the risk of malignancy (ROM) in PET-positive and PET-negative thyroid nodules. Further, preoperative characteristics indicative of thyroid malignancy were identified. METHODS: Thirty-two patients referred to thyroid surgery were prospectively included. 18FDG-PET/CT, fine-needle aspiration biopsy and thyroid ultrasonography examination were performed in all participants. The exact anatomical localization of the index nodule was established by histopathological examination to ensure concordance with the 18FDG-PET/CT finding. RESULTS: Forty thyroid nodules were included. Malignancy was identified in 10 of 28 PET-positive nodules and in 1 of 12 PET-negative nodules, resulting in a ROM of 36% and 8%, respectively. A Hurtle cell neoplasm was found in 50% of patients with a benign nodule and a PET-positive scan. One PET-negative nodule represented a papillary microcarcinoma. In PET-positive nodules, hypoechogenicity, irregular margins, and pathological lymph nodes on thyroid ultrasonography were characteristics associated with malignancy. CONCLUSIONS: In this study-ensuring anatomical congruity between PET-findings and the histopathological examination-the risk of malignancy in PET-positive thyroid nodules was 36%. A low ROM was seen in thyroid nodules without suspicious ultrasonographic findings, independent of the 18FDG-PET/CT result. TRIAL REGISTRATION NUMBER: NCT02150772 registered 14th of April 2014.

Acute airway obstruction due to spontaneous intrathyroidal haemorrhage.

A woman in her mid-80's collapsed while home due to a sudden onset of swelling on her neck compromising the airway. She was intubated on-site and brought to the trauma-centre where she was diagnosed with an intrathyroidal bleeding with compression of the trachea. A subacute left sided thyroid lobectomy was performed, giving immediate relief to the displaced and compressed airway. The patient was discharged after 3 days. The final histopathological examination revealed a microfollicular adenoma with extensive bleeding.

Incidental and Non-incidental Papillary Thyroid Microcarcinoma in Denmark 1996-2015: A national study on incidence, outcome and thoughts on active surveillance.

BACKGROUND: Incidental and non-incidental papillary microcarcinomas (PMC) are associated with different outcomes and treatment options may vary. The least favourable outcome is typically seen when carcinoma is suspected prior to surgery. Only a few studies have addressed the prognosis based on the way of detection for PMC, and they have been limited to retrospective single-center studies. We hypothesize that the "way of detection" may predict prognosis. The aim was to calculate the incidence and outcome of PMC based on the way of detection and to identify patients that may be suitable for active surveillance. METHOD: This national cohort study consists of 803 patients diagnosed with PMC in Denmark from 1996 to 2015. Patients were identified from the DATHYRCA database and allocated into groups according to the way of detection leading to surgery: Incidental at surgery (n = 527), non-incidental with symptoms suspected from the index tumor (n = 134) and non-incidental with symptoms suspected from a metastasis (n = 142). RESULTS: Age-standardized incidence rates increased from 0.35 per 100,000 per year in 1996 to 1.19 per 100,000 per year in 2015. A significant rise in incidence was found for both the incidental group and non-incidental group with symptoms suspected from a metastasis. Recurrence free survival was significantly worse for patients with suspicion of metastasis prior to surgery than patient groups without. No difference in mortality was found between groups. CONCLUSION: PMC patients without suspicion of metastasis have the same low risk of recurrence as incidental cases and may be candidates for active surveillance.

Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

BACKGROUND: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. METHODS: The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. RESULTS: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. CONCLUSION: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study.

Recent studies have shown a significant increase in the temporal trend of medullary thyroid carcinoma (MTC) incidence. However, it remains unknown to which extent sporadic medullary thyroid carcinoma (SMTC) and hereditary MTC (HMTC) affect the MTC incidence over time. We conducted a nationwide retrospective study using previously described RET and MTC cohorts combined with review of medical records, pedigree comparison and relevant nationwide registries. The study included 474 MTC patients diagnosed in Denmark between 1960 and 2014. In the nationwide period from 1997 to 2014, we recorded a mean age-standardized incidence of all MTC, SMTC and HMTC of 0.19, 0.13 and 0.06 per 100,000 per year, respectively. The average annual percentage change in incidence for all MTC, SMTC and HMTC were 1.0 (P = 0.542), 2.8 (P = 0.125) and -3.1 (P = 0.324), respectively. The corresponding figures for point prevalence at January 1, 2015 were 3.8, 2.5 and 1.3 per 100,000, respectively. The average annual percentage change in prevalence from 1998 to 2015 for all MTC, SMTC and HMTC was 2.8 (P < 0.001), 3.8 (P < 0.001) and 1.5 (P = 0.010), respectively. We found no significant change in the incidence of all MTC, SMTC and HMTC possibly due to our small sample size. However, due to an increasing trend in the incidence of all MTC and opposing trends of SMTC (increasing) and HMTC (decreasing) incidence, it seems plausible that an increase for all MTC seen by others may be driven by the SMTC group rather than the HMTC group.

Anaplastic thyroid carcinoma in Denmark 1996-2012: A national prospective study of 219 patients.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the least common but most malignant thyroid cancer. We aimed to examine the characteristics as well as evaluate the incidence, prognostic factors, and if introduction of a fast track cancer program might influence survival in a cohort of ATC patients. METHODS: A cohort study based on prospective data from the national Danish thyroid cancer database DATHYRCA and the national Danish Pathology Register including 219 patients diagnosed from 1996 to 2012, whom were followed until death or through September 2014. RESULTS: We found the median age in the 7th decade, the majority of patients being women presenting with a growing mass at the neck, diagnosed with stage T4b disease. At diagnosis, 56% of the patients had lymph node metastasis and 38% distant metastasis. We observed one- and five-year survival of 20.7% and 11.0%, respectively. Both univariate and multivariate analyses showed age (above 73.6 years), respiratory impairment, T4b stage, and distant metastasis at diagnosis to be significant prognostic factors. Further, introduction of a national fast track cancer program increased survival nearly two-fold. CONCLUSION: As new information, our study adds "respiratory impairment at diagnosis" and "introduction of a national fast track cancer program" to the list of already established prognostic indicators for ATC.

Nonanaplastic follicular cell-derived thyroid carcinoma: mitosis and necrosis in long-term follow-up.

Nonanaplastic follicular cell-derived thyroid carcinoma (NAFCTC) includes differentiated- (DTC) and poorly differentiated thyroid carcinoma (PDTC). DTC has an excellent prognosis, while PDTC is situated between DTC and anaplastic carcinomas. Short-term studies suggest that PDTC patients diagnosed only on tumor necrosis and/or mitosis have a prognosis similar to those diagnosed according to the TURIN proposal. The purpose of this study was to evaluate prognosis for NAFCTC based on long-term follow-up illuminating the significance of tumor necrosis and mitosis. A cohort of 225 patients with NAFCTC was followed more than 20 years. Age, sex, distant metastasis, histology, tumor size, extrathyroidal invasion, lymph node metastasis, tumor necrosis and mitosis were examined as possible prognostic factors. Median follow-up time for patients alive was 28 years (range 20-43 years). Age, distant metastasis, extrathyroidal invasion, tumor size, tumor necrosis and mitosis were independent prognostic factors in multivariate analysis for overall survival (OS). In disease specific survival (DSS) age was not significant. Using only necrosis and/or mitosis as criteria for PDTC the 5-, 10- and 20-year OS for DTC was 87, 79 and 69%, respectively. In DSS it was 95, 92 and 90%. For PDTC the 5-, 10- and 20-year OS was 57, 40 and 25%, respectively. In DSS it was 71, 55 and 48%. Tumor necrosis and mitosis are highly significant prognostic indicators in analysis of long time survival of nonanaplastic follicular cell-derived thyroid carcinoma indicating that a simplification of the actually used criteria for poorly differentiated carcinomas may be justified.

Gene-expression Classifier in Papillary Thyroid Carcinoma: Validation and Application of a Classifier for Prognostication.

BACKGROUND: No reliable biomarker for metastatic potential in the risk stratification of papillary thyroid carcinoma exists. We aimed to develop a gene-expression classifier for metastatic potential. MATERIALS AND METHODS: Genome-wide expression analyses were used. Development cohort: freshly frozen tissue from 38 patients was collected between the years 1986 and 2009. Validation cohort: formalin-fixed paraffin-embedded tissues were collected from 183 consecutively treated patients. RESULTS: A 17-gene classifier was identified based on the expression values in patients with and without metastasis in the development cohort. The 17-gene classifier for regional/distant metastasis identified was tested against the clinical status in the validation cohort. Sensitivity for detection of metastases was 51.5% and specificity 61.6%. Log-rank testing failed to identify any significance (p=0.32) regarding the classifier's usefulness as a prognostic marker for recurrence. CONCLUSION: A 17-gene classifier for metastatic potential was developed, and the results showed a clear biological difference between groups. However, through validation, no prognostic significance of this classifier was shown.

Papillary thyroid carcinoma in Denmark, 1996-2008: outcome and evaluation of established prognostic scoring systems in a prospective national cohort.

BACKGROUND: Regional as well as national series show an increasing incidence of thyroid cancer largely small size papillary thyroid carcinoma (PTC). Prognostic scoring systems have been developed, but these do not take into account the rapidly changing case mix, and adjustments may be required. The purposes of this study were to evaluate treatment outcomes and to analyze the value of older prognostic scoring systems tested on a relatively new, unselected national cohort of PTC patients. METHODS: This was a national prospective cohort study conducted in Denmark, which has a population of 5.5 million. RESULTS: A total of 1350 patients were diagnosed with PTC during 1996-2008, and the median follow-up time was 7.9 years. The 10-year recurrence-free survival rate was 90.2%, and the 10-year crude and cause-specific survival (CSS) rates were 83.7% and 93.8% respectively. By multivariate Cox regression, it was possible to confirm age, metastases (distant and nodal), extrathyroidal extension, and tumor size as predictors of mortality, whereas only nodal metastases, extrathyroidal extension, and tumor size were predictors of recurrence. In analyses of older prognostic scoring systems, a significant correlation between the risk group ranks was found for survival as well as recurrence. The c-index for CSS was highest for MACIS (0.92) and lowest for AMES (0.80). In the TNM, MACIS, and EORTC systems, most patients were classified as stage 1, and for these patients, the 10-year CSS rate was approximately 99.5%, confirming the generally excellent survival. CONCLUSION: This national study provides further evidence that a favorable prognosis is to be expected for patients diagnosed with PTC. Also, it was possible to confirm age, metastases, extrathyroidal extension, and tumor size as predictors of mortality, whereas only nodal metastases, extrathyroidal extension, and tumor size were predictors of recurrence. All the scoring systems evaluated were able to produce a highly significant risk group stratification, showing that in spite of the changes in the case mix of PTC, these systems are still applicable, and in fact contain valuable prognostic information useable for treatment planning.

Completeness and validity in a national clinical thyroid cancer database: DATHYRCA.

BACKGROUND: Although a prospective national clinical thyroid cancer database (DATHYRCA) has been active in Denmark since January 1, 1996, no assessment of data quality has been performed. The purpose of the study was to evaluate completeness and data validity in the Danish national clinical thyroid cancer database: DATHYRCA. STUDY DESIGN AND SETTING: National prospective cohort. Denmark; population 5.5 million. Completeness of case ascertainment was estimated by the independent case ascertainment method using three governmental registries as a reference. The reabstracted record method was used to appraise the validity. For validity assessment 100 cases were randomly selected from the DATHYRCA database; medical records were used as a reference. RESULT: The database held 1934 cases of thyroid carcinoma and completeness of case ascertainment was estimated to 90.9%. Completeness of registration was around or above 90% in most instances. Perfect agreement on the diagnosis of thyroid carcinoma was found, both inter- and intra-observer, and κ values of selected variables showed overall good to excellent agreement. CONCLUSION: In a setup with public health insurance, personal identity numbers and extended governmental databases, it is possible to establish national clinical cancer databases with a satisfactory completeness and validity. The DATHYRCA database is considered reliable in terms of describing thyroid carcinoma at a national level.

Papillary thyroid microcarcinoma in Denmark 1996-2008: a national study of epidemiology and clinical significance.

BACKGROUND: With an observed general rise in papillary thyroid carcinoma incidence, papillary microcarcinoma (PMC) is accordingly found more frequently and often incidentally by histological examination of surgical specimens from presumed benign thyroid disease. Only a few studies have specifically addressed the prognosis of incidentally found PMC, and they have been limited to retrospective single-center studies. METHODS: This was a national, unselected, prospective cohort study of 406 papillary thyroid microcarcinoma patients diagnosed in Denmark from 1996 to 2008. OBJECTIVE: The aim of this study was to evaluate incidence, outcome, and extent of necessary treatment, with special attention given to incidentally detected PMC. RESULTS: Age-standardized ratios were found to increase from 0.35 per 100,000 per year in 1996 to 0.74 per 100,000 per year in 2008. A total of 240 out of 406 cases were found incidentally, and a significant rise in incidence was only found for the incidental cases. Median follow-up was 7.6 years for the incidental cases, and in this time span, five cases of recurrence and no deaths from thyroid cancer occurred. The five-year recurrence-free survival was 98.1%, and only occurrence of lymph-node metastasis was found to affect the recurrence rate. A total of 160 incidental cases were initially treated with lobectomy, and the incidence of recurrence was not significantly different in the cases receiving completion thyroidectomy. CONCLUSION: The rising incidence of PMC in Denmark is explained by incidental cases. When the carcinoma is not the index tumor for surgery, this study implies that completion thyroidectomy does not improve prognosis.

Papillary thyroid carcinoma in Denmark 1996-2008: an investigation of changes in incidence.

BACKGROUND: A rise in the incidence of thyroid cancer has been reported in several countries, and the increase is only seen in the papillary type. Increased detection due to higher resolution ultrasound and fine needle aspiration has been proposed as the explanation, recent registry studies however question this assumption. METHODS: National, unselected, prospective cohort study of 1350 papillary thyroid cancer patients in Denmark from 1996 to 2008. OBJECTIVE: To analyze changes in incidence by time and to identify factors which might influence detection rate. RESULTS: A rise in incidence is seen with age standardized ratios increasing from 1.43 per 100.000 per year in 1996 to 2.16 per 100.000 per year in 2008. The median age at presentation was 46 years and median tumor size was 18 mm. Male/female ratio was 1/2.9. By dichotomizing the material in a time period before and after the 30th of June 2001, no significant change in the proportion of diagnosed tumors smaller than 1 or 2 cm was found, and 42.8% of the rise in incidence was explained by tumors larger than 2 cm. No significant change in diagnostic use of ultrasound or fine needle aspiration was found, and a significant change toward more extensive thyroid surgery could not be confirmed. CONCLUSION: This study shows a significant rise in incidence of papillary thyroid carcinoma in Denmark from 1996 to 2008, which is not explained by increased use of preoperative diagnostic modalities. Other reasons need to be considered.

Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease?

INTRODUCTION: Papillary microcarcinomas (PMC) of the thyroid gland are defined according to The WHO Committee as papillary carcinomas measuring 10 mm or less in diameter. A large proportion of these tumours are found coincidentally in the treatment of symptomatic goitre and most cases follow an indolent course with an excellent prognosis. However, a more aggressive behaviour with regional and distant metastases does occur. The aim of this study was to evaluate if the immunohistochemical markers cyclin D1 or galectin-3 might indicate the presence of metastatic disease in patients with PMC at the time of diagnosis. MATERIAL AND METHODS: From the 1(st) of January 1996 to 31(st) of December 2002 a total of 169 PMC patients were diagnosed and registered in the national Danish thyroid cancer database DATHYRCA and 131 of these were eligible for the study. Forty-three (33%) had histologically verified regional or distant metastases. Slides were cut from the primary tumour and immunostaining and quantification was subsequently performed. RESULTS: The percentage of positive cells was examined for patients with and without metastases. For cyclin D1 the median values were 31% (range: 0-59) and 21% (range: 0-75), respectively, showing a statistically significant difference (p=0.02). For galectin-3 the medians were 87% (range: 6-96) and 85% (range: 0-99) and no significant difference was found. CONCLUSION: Cyclin D1 showed significantly higher median expression in patients with metastases compared to those without, indicating a correlation to tumour aggressiveness. However, both groups showed large variation in expression, which disqualify the marker as a discriminator for the detection of metastases. Galectin-3 was without any significant correlation to the presence of metastases from PMC.