Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma.

AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.

The Clinical Utility of Gallium-68-DOTATATE Positron Emission Tomography Scanning in Medullary Thyroid Cancer.

OBJECTIVE: Somatostatin receptor (SST) functional imaging with positron emission tomography (PET)/computed tomography (CT) has broadened the diagnostic and staging capabilities for medullary thyroid cancer (MTC). Gallium-68 (68Ga)-DOTA-conjugated peptide (Tyr3)-octreotate (DOTATATE) is a radiotracer with a high affinity for type 2 SSTs expressed in several, but not all, MTCs. The utility of 68Ga-DOTATATE PET/CT and 18fluorine-labeled fluoro-2-deoxy-D-glucose (18F-FDG)-PET/CT imaging in predicting MTC prognosis is also unknown. METHODS: In this single-center retrospective study, 103 of patients with MTC underwent assessment of SST2 and SST5 immunohistochemistry (IHC). A subgroup of 37 patients received 68Ga-DOTATATE PET/CT imaging, and 13 received contemporaneous 18F-FDG-PET/CT imaging. The maximum standardized uptake value (SUV), mean SUV, metabolic tumor volume, and total lesion activity (TLA) were assessed. RESULTS: Forty-two patients (41%) demonstrated positive expression of SST2, and 45 (44%) had a positive SST5 IHC result. Seventeen patients (17%) expressed both SST2 and SST5. No survival advantage was identified with SST2 or SST5 IHC positivity. No correlation was noted between the maximum SUV, mean SUV, metabolic tumor volume, or TLA and SST2 and/or SST5 expression by IHC. Shorter survival was associated with a TLA of >20 (P = .04). A RET-negative status also appeared to have shorter survival, although this may be because the small numbers did not reach statistical significance (P = .12). CONCLUSION: Assessment of TLA from 68Ga-DOTATATE PET/CT may predict survival. SST2 IHC was not correlated with 68Ga-DOTATATE avidity. Metastatic disease may be optimally assessed by concurrent 18F-FDG and 68Ga-DOTATATE imaging.

Management of Medullary Thyroid Cancer: Patterns of Recurrence and Outcomes of Reoperative Surgery.

BACKGROUND: There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center. PATIENTS AND METHODS: A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data. RESULTS: In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018). CONCLUSION: Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control.

Ki67 proliferation index in medullary thyroid carcinoma: a comparative study of multiple counting methods and validation of image analysis and deep learning platforms.

AIMS: The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. However, manual counting remains a tedious and time-consuming task. METHODS AND RESULTS: We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning-based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near-perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease-specific survival and distant metastasis-free survival. CONCLUSIONS: We herein validate a machine learning-based deep-learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3-7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.

Genotype-Phenotype Correlations and Clinical Outcomes in 155 Cases of Pheochromocytoma and Paraganglioma.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours, often associated with germline mutations that influence the disease biology and clinical course. We aimed to describe the genotypic and phenotypic characteristics of a consecutive series of PPGL patients and correlate mutation status with clinical outcomes. METHODS: We performed a retrospective cohort study of all PPGL patients who presented to a tertiary referral centre between March 2005 and February 2022. Genotypic, phenotypic and follow-up data were analysed. RESULTS: A total of 140 patients were included. Of these, 94 (67%) patients underwent genetic testing and a mutation was detected in 36 (38%) patients. Mutation presence was associated with younger age, smaller tumour size and bilateral adrenal tumours. Disease recurrence occurred at a median time of 5.4 (IQR 2.8-11.0) years after treatment in 21 (15%) patients, of which 14 (67%) had a mutation in a susceptibility gene. Recurrence pattern was influenced by mutation type; higher local recurrence risk for SDHA, SDHB, and MEN2B disease, and higher metastatic risk for SDHB, VHL and MEN2A disease. Recurrence occurred in three (3%) patients with mutation absence. Multivariate analysis revealed that age ≤40 years and mutation presence were associated with increased risk of disease recurrence. CONCLUSIONS: Genotypic characteristics strongly influence disease presentation and recurrence risk, which may occur more than 5 years after initial treatment. Routine genetic testing of PPGL patients is warranted given the high prevalence of mutations, allowing for prognostication and tailored follow-up. In the presence of germline mutations, follow-up should be life-long.

The Prognostic Impact of Extent of Vascular Invasion in Follicular Thyroid Carcinoma.

BACKGROUND: Encapsulated angioinvasive follicular thyroid carcinoma (EAFTC) is associated with an increased risk of distant metastasis and reduced survival compared to minimally invasive follicular thyroid carcinoma (MIFTC). There is controversy regarding the extent of surgery and adjuvant radioactive iodine therapy for angioinvasive follicular thyroid carcinoma when stratified by number of foci of angioinvasion. METHODS: All follicular thyroid carcinoma cases from 1990-2018 were identified from a thyroid cancer database. Primary outcomes were distant metastasis-free survival (DMFS) and disease-specific survival (DSS) with factors of interest being age, gender, tumour size, treatment, foci of angioinvasion and histological subtype. RESULTS: A total of 292 cases were identified; 139 MIFTC, 141 EAFTC and 12 widely invasive follicular thyroid carcinoma (WIFTC). Over a follow-up period of 6.25 years, DMFS was significantly reduced (p < 0.001) with 14.2% (EAFTC) and 50% of WIFTC developing metastasis. The risk of metastasis in EAFTC with ≥ 4 foci of angioinvasion was 31.7% (HR = 5.89, p = 0.004), 6.3% for EAFTC with < 4 foci of angioinvasion (HR = 1.74, p = 0.47), compared to 3.6% MIFTC. Age ≥ 50 years (HR = 4.24, p = 0.005) and tumour size (HR = 1.27, p = 0.014) were significantly associated with increased risk of distant metastasis. DSS was reduced significantly (p < 0.001), with 7.8% EAFTC patients dying of disease. For EAFTC patients, DSS was 96.8% for < 4 foci and 82.6% for ≥ 4 foci of angioinvasion (p = 0.003). CONCLUSION: EAFTC is at increased risk of distant metastasis related to the extent of angioinvasion. Tumours with < 4 foci of angioinvasion should be considered for a total thyroidectomy, particularly in older patients.

Outcomes of Advanced Medullary Thyroid Carcinoma in the Era of Targeted Therapy.

BACKGROUND: Medullary thyroid carcinoma (MTC) can be targeted with tyrosine kinase inhibitors (TKIs). We aimed to report the outcomes of surgically managed MTC and to evaluate the impact of TKI use on patient survival. METHODS: Consecutive patients treated surgically for MTC from 1986 to 2020 were identified from a prospectively collected database and were compared on the basis of stage at operation and TKI use. The primary outcome was overall survival (OS). RESULTS: Among 154 patients with a median age of 52 years, 40% presented with stage I/II disease and 60% presented with advanced (stage III or IV) disease. During a median follow-up of 7.5 years, 21% received TKIs for systemic disease. Those presenting with advanced disease were more likely to receive a TKI (31% vs. 7%), present with tumor invasion of the recurrent laryngeal nerve (RLN; 12% vs. 0%) and undergo reoperation (42% vs. 23%) compared with stage I-II patients. For the 11 patients found to have invasion of the RLN, five had preoperative functional vocal cords. Five-year OS was 84% for advanced disease, and stage IV patients who received TKIs had a median survival of 21 years, versus 15 years for those who did not (p = 0.3). CONCLUSIONS: Surgery achieves long-term survival for patients with advanced disease, however these patients are at greater risk of requiring RLN resection due to invasion. A significant OS benefit was not seen for TKI use. For patients with local invasion, neoadjuvant TKI therapy may have a role in reducing local morbidity if confirmed to be of benefit in clinical trials.

Unexpected deaths after endocrine surgery: learning from rare events using a national audit of surgical mortality.

BACKGROUND: The mortality rate is low in endocrine surgery, making it a difficult outcome to use for quality improvement in individual units. Lessons from population data sets are of value in improving outcomes. Data from the Australian and New Zealand Audit of Surgical Mortality (ANZASM) were used here to understand and elucidate potential systems issues that may contribute to preventable deaths. METHODS: ANZASM data relating to 30-day mortality after thyroidectomy, parathyroidectomy, and adrenalectomy from 2009 to 2020 were reviewed. Mortality rates were calculated using billing data. Thematic analysis of independent assessor reports was conducted to produce a coding framework. RESULTS: A total of 67 deaths were reported, with an estimated mortality rate of 0.03-0.07 per cent (38 for thyroidectomy (0.03-0.06 per cent), 16 for parathyroidectomy (0.03-0.06 per cent), 13 for adrenalectomy (0.15-0.33 per cent)). Twenty-seven deaths (40 per cent) were precipitated by clinically significant adverse events, and 18 (27 per cent) were judged to be preventable by independent ANZASM assessors. Recurrent themes included inadequate preoperative assessment, lack of anticipation of intraoperative pitfalls, and failure to recognize and effectively address postoperative complications. Several novel themes were reiterated, such as occult ischaemic heart disease associated with death after parathyroid surgery, unexpected intraoperative difficulties from adrenal metastasis, and complications due to anticoagulation therapy after thyroid surgery. CONCLUSION: This study represents a large-scale national report of deaths after endocrine surgery and provides insights into these rare events. Although the overall mortality rate is low, 27 per cent of deaths involved systems issues that were preventable following independent peer review.

Preoperative metabolic classification of thyroid nodules using mass spectrometry imaging of fine-needle aspiration biopsies.

Thyroid neoplasia is common and requires appropriate clinical workup with imaging and fine-needle aspiration (FNA) biopsy to evaluate for cancer. Yet, up to 20% of thyroid nodule FNA biopsies will be indeterminate in diagnosis based on cytological evaluation. Genomic approaches to characterize the malignant potential of nodules showed initial promise but have provided only modest improvement in diagnosis. Here, we describe a method using metabolic analysis by desorption electrospray ionization mass spectrometry (DESI-MS) imaging for direct analysis and diagnosis of follicular cell-derived neoplasia tissues and FNA biopsies. DESI-MS was used to analyze 178 tissue samples to determine the molecular signatures of normal, benign follicular adenoma (FTA), and malignant follicular carcinoma (FTC) and papillary carcinoma (PTC) thyroid tissues. Statistical classifiers, including benign thyroid versus PTC and benign thyroid versus FTC, were built and validated with 114,125 mass spectra, with accuracy assessed in correlation with clinical pathology. Clinical FNA smears were prospectively collected and analyzed using DESI-MS imaging, and the performance of the statistical classifiers was tested with 69 prospectively collected clinical FNA smears. High performance was achieved for both models when predicting on the FNA test set, which included 24 nodules with indeterminate preoperative cytology, with accuracies of 93% and 89%. Our results strongly suggest that DESI-MS imaging is a valuable technology for identification of malignant potential of thyroid nodules.

Bi-national Review of Phaeochromocytoma Care: Is ICU Admission Always Necessary?

BACKGROUND: Post-operative management after phaeochromocytoma resection includes monitoring of blood pressure and blood sugar, and vigilance for haemorrhage. Guidelines recommend 24 h of continuous blood pressure monitoring, usually necessitating HDU/ICU admission. We hypothesised that most patients undergoing phaeochromocytoma resection do not require post-operative HDU/ICU admission. We aim to describe current Australian and New Zealand perioperative management of phaeochromocytoma and determine whether it is safe to omit HDU/ICU care for most patients. METHODS: We collected retrospective data on patients undergoing excision of phaeochromocytoma in 12 centres around Australia and New Zealand between 2007 and 2019. Data collected included preoperative medical management, anaesthetic management, vasopressor support, HDU/ICU admission and complications. RESULTS: A total of 223 patients were included in the study, 173 (77%) of whom were admitted to HDU/ICU post-operatively. The group of patients treated in ICU was similar to the group of patients treated on the ward in terms of demographic and tumour characteristics, and there were significant differences in the proportion of patients admitted to HDU/ICU between centres. Of patients admitted to ICU, 71 (41%) received vasopressor support. This was weaned within 24 h in 55 (77%) patients. Patients with larger tumours (> 6 cm) and a transfusion requirement are more likely to require prolonged inotropic support. Among patients admitted to the ward, there were no complications that required escalation of care. CONCLUSIONS: Although not widespread practice in Australia and New Zealand, it appears safe for the majority of patients undergoing minimally invasive resection of phaeochromocytoma to be admitted to the ward post-operatively.

The Significance of Histologically "Large Normal" Parathyroid Glands in Primary Hyperparathyroidism.

INTRODUCTION: We investigated outcomes in a cohort of patients with a biochemical diagnosis of primary hyperparathyroidism (pHPT) undergoing surgery for asymptomatic disease or target organ damage, where a focussed or four-gland operation was undertaken and the histopathology only reported a "large normal" parathyroid gland (LNP). METHODS AND MATERIALS: Patients subjected to a parathyroidectomy for pHPT between 2012 and 2018 with a pathology of LNP were included. Patients with fat depletion or additional histological features of adenoma or hyperplasia in any of the resected glands were excluded. A control group was formed from 50 consecutive patients with the histological finding of adenoma or hyperplasia during the same study period. The primary outcome was biochemical normalisation of pHPT at 1-2 weeks and after 6 months post-operatively. RESULTS: Forty-eight LNP patients (2% of all parathyroidectomies) were included in the study group with 50 matched controls. LNP patients had a lower biochemical cure rate (81% vs. 98% P < 0.05) and a higher risk of recurrence (10% vs. 0%, P = 0.06). LNP patients had a milder form of pHPT (Ca2+ 2.63 vs. 2.68 P < 0.05) with a smaller PTH and Ca2+ drop post-operatively. For LNP patients with failure, a definite additional cause of pHPT was found in only two patients. CONCLUSION: This study highlights a controversial area in pHPT and reports LNP as a cause of pHPT. The biochemical analysis of this LNP group supports a benefit in resection in the setting of pHPT, although the risk of failure (persistence/recurrence) is higher than those with adenoma or hyperplasia. Stricter post-operative follow-up of LNP patients should be considered.

microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens. MATERIALS AND METHODS: Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a "sensitive" and "resistant" cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. RESULTS: microRNA-431 (miR-431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR-431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial-mesenchymal transition underlies the action of miR-431 with doxorubicin treatment, with Zinc Finger E-Box Binding Homeobox 1 implicated as the molecular target of miR-431 in ACC. CONCLUSION: This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well-studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings. IMPLICATIONS FOR PRACTICE: Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence-free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.

Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression.

Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERß expression in the MTC tumour. ERα and ERß form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERß represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.

Role of DOTATATE-PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas.

CONTEXT: Diagnosis of paragangliomas (PGL) and phaeochromocytomas (PC) can be challenging particularly if the tumour is small. Detection of metastatic disease is important for comprehensive management of malignant PC/PGL. Somatostatin receptor imaging (SRI) agents have high sensitivity for these tumours, particularly the DOTA family of radiopharmaceuticals labelled with 68 Gallium. OBJECTIVE: To describe the utility of SRI in primary assessment (ie before surgery) for PC/PGL and whether measures of maximum standardized uptake (SUVmax) could be used to distinguish between adrenal adenomas and PCs. DESIGN: Retrospective analysis of patients with PC and PGL between 2012 and 2017. PATIENTS: Somatostatin receptor imaging (SRI) was performed for suspected PC (n = 46) or PGL (n = 27) of which 36 were during primary assessment and 37 during secondary assessment (follow-up after surgery). For comparison of adrenal SUVmax, scans from 30 patients without suspected PC/PGL (20 with normal adrenals; 10 with incidental adenomas) were evaluated. MEASUREMENTS: Baseline description, sensitivity, specificity, Youden's index. RESULTS: Sensitivity of DOTATATE-PET was 88% for PC and 100% for PGL. False-negative scans were seen in 2/10 PCs < 28 mm and in 1/14 PCs > 28 mm which had features of cystic degeneration. SUVmax of PCs and PGLs was more than double compared to adrenal adenomas (P > .001). CONCLUSION: Somatostatin receptor imaging (SRI) has high sensitivity in primary assessment for PC and PGL. We recommend that SRI should be performed as part of primary assessment in all suspected PGLs (due to higher risk of multifocal lesions) and in PCs suspected to be associated with hereditary syndromes or metastases.

Disease Progression in Papillary Thyroid Cancer with Biochemical Incomplete Response to Initial Therapy.

BACKGROUND: Dynamic risk stratification is utilized in the follow-up of patients with papillary thyroid carcinoma (PTC). Analysis of outcomes after biochemical incomplete response (BIR) to initial therapy will allow better individualization of care. METHODS: A total of 494 patients with PTC were followed prospectively. Immunohistochemistry (IHC) for BRAFV600E mutation was completed on all surgical specimens. After exclusion of patients with inadequate data, 353 patients were stratified into four categories of response to initial therapy: excellent, biochemical incomplete, structural incomplete, or indeterminate. Patients with BIR, defined as elevated stimulated thyroglobulin >2 µg/L with negative imaging, were analysed for progression of disease. The primary outcome measure was development of structural recurrence. RESULTS: Forty-nine of 353 (13.9%) patients had BIR. BRAFV600E mutation was present in 32 of 49 (65.3%) with BIR. Progression to structural recurrence occurred in 8 of 49 (16.3%) with BIR, all of whom were positive for the BRAFV600E mutation (p = 0.02). Nine patients (18%) with BIR remitted during follow-up to no evidence of disease (6 had additional RAI therapy). After mean follow-up of 35 months, 12 patients with BIR (24%) remained biochemically abnormal with no structural evidence of disease. CONCLUSIONS: Patients with BIR following initial treatment for PTC have generally favorable outcomes. Positive IHC for BRAFV600E identifies patients at risk of structural disease recurrence.

Incidence and Risk Factors for Occult Level 3 Lymph Node Metastases in Papillary Thyroid Cancer.

BACKGROUND: Papillary thyroid cancer (PTC) frequently disseminates into cervical lymph nodes. Lateral node involvement is described in up to 50 % patients undergoing prophylactic lateral neck dissection. This study aimed to assess this finding and identify which factors predict for occult lateral node disease. METHODS: Patients with fine needle aspiration-confirmed PTC (Bethesda V or VI), without evidence of cervical lymph node metastases, underwent a total thyroidectomy with prophylactic ipsilateral central and level 3 dissection. Level 3 nodes were removed by compartmental dissection or by sampling the sentinel nodes overlying the jugular vein, according to surgeon preference. Data were collected prospectively from January 2011 to August 2014. Statistical analysis was performed by SPSS software. RESULTS: A total of 137 patients underwent total thyroidectomy with prophylactic ipsilateral central and level 3 dissection for PTC. The incidence of occult level 3 disease was 30 % (41/137 patients). A total of 48 % of patients (66/137) harbored occult central neck disease. A total of 80.5 % of patients with pN1b disease had macrometastases (≥2 mm), and 15 % exhibited skip metastases with central compartment sparing. In patients with pN1b disease, a median of 6 level 3 nodes were retrieved, with an average involved nodal ratio of 0.29. Multivariate regression demonstrated risk factors for occult lateral neck metastasis include tumor size (odds ratio 1.1), upper pole tumors (odds ratio 6.6), and vascular invasion (odds ratio 3.2) (p < 0.05). CONCLUSIONS: PTC is associated with a significant incidence of occult central and lateral nodal metastases. In patients undergoing prophylactic central neck dissection, inclusion of level 3 dissection should be considered in patients with large upper lobe cancers.

TERT promoter mutations are a major indicator of recurrence and death due to papillary thyroid carcinomas.

CONTEXT: TERT promoter mutations have been associated with adverse prognosis in papillary thyroid carcinomas (PTCs). OBJECTIVE: We investigated the association between TERT promoter mutations and survival from PTC. DESIGN: Retrospective observational cohort study. PATIENTS: Eighty consecutive patients with PTC who underwent surgery between 1990 and 2003. MEASUREMENTS: TERT promoter was genotyped in DNA from 80 archival PTCs by Sanger sequencing. Median follow-up was 106 months (range 1-270). Outcomes analysis was stratified according to disease and overall survival status. For each parameter, relative risk (RR) adjusted for age at first surgery and gender was estimated. Both univariate and multivariate analyses were performed using logistic regression, Kaplan-Meier survival analysis and Cox regression models. RESULTS: PTCs from 11 patients (14%) contained either C228T or C250T TERT promoter mutation. TERT mutations were significantly associated with adverse prognostic features such as older age (P = 0·002), male gender (P = 0·01) and Stage IV disease (P = 0·03). Four patients died from PTC during follow-up: 3 patients with TERT mutations (27%) and one without (1·5%). Disease-related mortality rate with or without TERT mutations was 33·7 vs 1·6 per 1000 patient-years respectively, that is 10 (95% CI = 1·0-104·1, P = 0·05) fold higher, after adjustment for age at first surgery and gender. The combination of TERT promoter mutation and BRAF(V) (600E) significantly increased disease-related death risk (P = 0·002). TERT mutations increased expression of a reporter gene in thyroid cells containing BRAF(V) (600E) . CONCLUSIONS: TERT promoter mutations are a major indicator of death due to PTCs. Conversely, absence of TERT mutations portends better survival.