Well-differentiated Papillary Thyroid Cancer Research Articles

SAT576 Change Is Not Always For The Best! A Transformation of Papillary Into Metastatic Anaplastic Thyroid Carcinoma

Abstract Disclosure: J. Syeda: None. R. Zafar: None. K. Rajamani: None. INTRODUCTION: Anaplastic thyroid carcinoma (ATC) can occur de-novo or from preexisting well-differentiated thyroid carcinoma (1). The presence or absence of certain driver mutations can help predict the likelihood of this transformation process. We present a case of an elderly female with an initial diagnosis of well-differentiated papillary thyroid cancer (PTC) with a transformation into metastatic anaplastic thyroid carcinoma (ATC). CASE PRESENTATION: An 81-year-old female patient was initially seen 8 years ago with a 35-year history of goiter. At the initial presentation, she felt well and did not have any symptoms. Physical examination revealed an enlarged thyroid gland with left lobe nodularity. A thyroid ultrasound showed a multinodular thyroid gland including a 2x1.7x1.2 cm solid nodule with macro calcifications in the right lobe, 2.8x2.6x2.5 cm solid nodule, and 1.6x1.3x1.6 cm heterogeneous solid nodule with calcifications and irregular margins in the left lobe. She had a fine needle aspiration of these three nodules. The right nodule was non-diagnostic and both left nodules were positive for PTC. She underwent a total thyroidectomy and central lymph node dissection. Radioactive iodine treatment with 163mCi was administered after surgery. One and a half years after surgery, her thyroglobulin levels started trending upward. This led to a further workup including a PET/CT scan, which showed a hyper metabolic 6 mm left supraclavicular lymph node. Needle biopsy of this lymph node disclosed metastatic PTC. The pathologic diagnosis following surgical resection was positive for metastatic poorly differentiated thyroid carcinoma. A subsequent PET/CT scan and a thyroid ultrasound showed an abnormal uptake of the left neck lymph node and additional metastatic nodes in the left neck respectively. A core needle biopsy of these lesions was positive for ATC. Foundation One CDx testing was positive for BRAF V600E, TP53, and TERT promoter mutations. Cellblock from the initial thyroidectomy was reevaluated by pathology and confirmed no evidence of ATC. Foundation One CDx testing of the thyroidectomy specimen was positive for BRAF V600E and TERT promoter mutations. Surveillance imaging shows mediastinal adenopathy, left pleural thickening, and bone and liver metastases. DISCUSSION: Anaplastic transformation is not uncommon (1). This case supports the evidence that TERT promoter mutations may not trigger anaplastic transformation but may predispose to the aggressive PTC phenotype prone to conversion to ATC when one of the ATC-related “second hit” genetic events occurs (2). This case suggests that the “second hit” event is a TP53 mutation. The detection of a TP53 mutation in PTC with an aggressive phenotype may help predict anaplastic transformation. REFERENCES: 1-Endocrine Pathology. 2021 Mar; 32(3):347-356. 2- Semin Cancer Biol. 2020 Apr; 61: 23-29. Presentation: Saturday, June 17, 2023

Artificial intelligence (AI) analysis of tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) slides to explore immune phenotypes in papillary thyroid cancer.

6100 Background: Different biomarkers have been discovered to predict response to immunotherapy but the variability of response exists. TILs are a potential biomarker as infiltration of CD8+ T cells in the tumor microenvironment(TME) was related to treatment response to PD-1 blockade. Advanced well-differentiated papillary thyroid cancer(PTC) has limited standard-of-care treatment options and can exhibit a poor prognosis when exhausted. Our study aimed to classify the TME of PTC according to TILs. Methods: Using the TCGA PTC data, samples were classified into three immune phenotypes (immune-’desert’, immune-’excluded’, and ‘inflamed’) based on peri-tumor lymphocyte density from analysis of H&E slides using an AI model(Lunit SCOPE). Immune and stromal cell infiltration was inferred using xCell. Cytolytic scores(CYT) and thyroid differentiation scores(TDS) were calculated using mRNA expression. Results: Total of 383 samples were included. Immune phenotype analysis showed 183(47.7%) ‘desert’, 133(34.7%) ‘excluded’, and 67(17.4%) ‘inflamed’. Median age at diagnosis was the lowest in ‘inflamed’(inflamed 41.5 vs excluded 47 vs desert 50, p = 002). TNM stages were as follows in the order of stages 1 to 4: inflamed 49/4/8/3, excluded 64/13/32/16, and desert 86/28/40/19. BRAF V600E mutation was most prevalent in ‘excluded’(97/133, 72%), followed by ‘inflamed’(32/67, 47.7%) and ‘desert’(51/183, 27.8%). CYT was the highest in ‘inflamed’(median: inflamed 186 vs excluded 53 vs desert 39, p < 0.001). TDS was the highest in ‘desert’(median: inflamed -0.3 vs excluded -0.69 vs desert 0.73, p < 0.001). The 6 cell types with the most statistically significant difference in infiltration were activated dendritic cells(aDCs), DCs, B cells, epithelial cells(EpCs), CD8+ central memory T cells, and CD4+ memory T cells. The ‘inflamed’ showed the highest median value for all of these cells except EpCs. The cells with the highest median value in ‘excluded’ included EpCs, sebocytes, and immature DCs. The cells with the highest median value in ‘desert’ were lymphatic endothelial cells(ECs), ECs, and osteoblasts. Three immune phenotypes were associated with differential outcomes in disease-free survival(log-rank for trend, p-value = 0.01). There was no difference in overall survival. Conclusions: Our results suggest that 15% of PTC can have immune features which were related to a higher rate of response to immunotherapy across different tumor types. A previous study showed that PTC with a low TDS or BRAF V600E mutation is related to increased immune response indices. In our study, TDS or BRAF V600E mutation status could not distinguish the ‘inflamed’ from other phenotypes. This suggests that immune phenotype classification through TILs can provide distinct information about the TME of PTC.

The effect of thyroid hormone withdrawal performed to evaluate the success of I-131 ablation on quality of life and psychological symptoms in female patients with low-risk differentiated thyroid cancer

Aim: There is a need to evaluate the treatment response in patients who have undergone radioiodine treatment (RIT) for differentiated thyroid cancer. Diagnostic tests that are used for this purpose include radioiodine whole-body scan (WBS) and serum thyroglobulin (Tg) measurement, which are most accurate during thyroid-stimulating hormone (TSH) stimulation. However, temporary discontinuation of thyroid hormone therapy to increase TSH (withdrawal) may be associated with the morbidity of hypothyroidism. The study aimed to show the effects of thyroid hormone withdrawal (THW) on quality of life and psychological symptoms in female patients with low-risk, well-differentiated papillary thyroid cancer. Methods: We applied the short form-36 (SF-36) and Symptom Checklist-90-R (SCL-90-R) questionnaires to the patients in the euthyroid state who have referred a median of 9 months (6-13 months) after RIT to perform a dWBS and to evaluate stimulated Tg. We applied the same questionnaire again when thyroid-stimulating hormone (TSH) was > 30 μIU/mL 4 weeks after THW (hypothyroid state). Results: 52 patients were evaluated (median age 48 years, range 23-65 years). There was a statistically significant worsening in anxiety, psychosis, additional items, and general symptoms of the SCL-90-R questionnaire, physical functioning, role limitation due to physical health, energy/fatigue, emotional well-being, social function, and general health change in the SF-36 questionnaire. Conclusions: THW worsened the patients’ psychological symptoms and quality of life. To reduce the side effects of hypothyroidism, treatment response assessment with TSH stimulation should be used only in a selected group of patients with a higher risk of recurrence.

Serum Linkage-Specific Sialylation Changes Are Potential Biomarkers for Monitoring and Predicting the Recurrence of Papillary Thyroid Cancer Following Thyroidectomy.

BackgroundAlthough papillary thyroid cancer (PTC) could remain indolent, the recurrence rates after thyroidectomy are approximately 20%. There are currently no accurate serum biomarkers that can monitor and predict recurrence of PTC after thyroidectomy. This study aimed to explore novel serum biomarkers that are relevant to the monitoring and prediction of recurrence in PTC using N-glycomics.MethodsA high-throughput quantitative strategy based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to obtain serum protein N-glycomes of well-differentiated PTC, postoperative surveillance (PS), postoperative recurrence (PR), and matched healthy controls (HC) including linkage-specific sialylation information.ResultsSerum N-glycan traits were found to differ among PTC, PS, PR, and HC. The differentially expressed N-glycan traits consisting of sixteen directly detected glycan traits and seven derived glycan traits indicated the response to surgical resection therapy and the potential for monitoring the PTC. Two glycan traits representing the levels of linkage-specific sialylation (H4N3F1L1 and H4N6F1E1) which were down-regulated in PS and up-regulated in PR showed high potential as biomarkers for predicting the recurrence after thyroidectomy.ConclusionsTo the best of our knowledge, this study provides comprehensive evaluations of the serum N-glycomic changes in patients with PS or PR for the first time. Several candidate serum N-glycan biomarkers including the linkage-specific sialylation have been determined, some of which have potential in the prediction of recurrence in PTC, and others of which can help to explore and monitor the response to initial surgical resection therapy. The findings enhanced the comprehension of PTC.

Invasion of a Recurrent Laryngeal Nerve from Small Well-Differentiated Papillary Thyroid Cancers: Patient Selection Implications for Active Surveillance.

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since preoperative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on preoperative examination. Invasion of the RLN was not observed for primary tumors <0.9 cm in diameter, regardless of tumor location. Conclusions: Well-differentiated PTC tumors ≥0.9 cm in maximal diameter that are located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions are usually not appropriate for active surveillance even in the absence of definitive evidence for nerve invasion on preoperative imaging or vocal cord examination. Patient selection for active surveillance management should take into account not only the size and growth rate of a tumor but also its location in relation to the expected course of RLNs.

A novel gene panel for prediction of lymph-node metastasis and recurrence in patients with thyroid cancer

BackgroundAlthough well-differentiated papillary thyroid cancer may remain indolent, lymph node metastases and the recurrence rates are approximately 50% and 20%, respectively. No current biomarkers are able to predict metastatic lymphadenopathy and recurrence in early stage papillary thyroid cancer. Hence, identifying prognostic biomarkers predicting cervical lymph-node metastases would prove very helpful in determining treatment. MethodsThe database of the Cancer Genome Atlas included 495 papillary thyroid cancer samples. Using this database, we developed a machine learning model to define a gene signature that could predict lymph-node metastasis (N0 or N1). Kruskal-Wallis tests, univariate and multivariate logistic and Cox regression models, and Kaplan-Meier analyses were performed to correlate the gene signature with clinical outcomes. ResultsWe identified a panel of 25 genes and constructed a risk score that can differentiate N0 and N1 papillary thyroid cancer samples (P < .001) with a sensitivity of 86%, a specificity of 62%, a positive predictive value of 93%, and a negative predictive value of 42%. This panel represents an independent biomarker to predict metastatic lymphadenopathy (OR = 8.06, P < .001) specifically in patients with T1 lesions (OR = 7.65, P = .002) and disease-free survival (HR = 2.64, P = .043). ConclusionThis novel 25-gene panel may be used as a potential prognostic marker for accurately predicting lymph-node metastasis and disease-free survival in patients with early-stage papillary thyroid cancer.

Tyrosine Kinase Inhibitor Therapy in Locally Advanced Differentiated Thyroid Cancer: A Case Report

A 73-year-old female presenting with haemoptysis and dyspnoea was found to have a locally advanced left thyroid mass and vocal cord palsy. A CT scan of the neck and thorax and endoscopy demonstrated invasion into the tracheal lumen. Histopathology of the intraluminal tracheal mass confirmed a papillary thyroid cancer (PTC). The tumour was deemed unresectable due to local extent and patient comorbidities. TKI therapy with lenvatinib was used for 14 months. On serial scanning, a marked reduction in tumour volume from 31 × 59 × 32 mm to 17 × 28 × 22 mm was noted. This subsequently allowed a successful surgical resection with a total thyroidectomy and central neck dissection with no evidence of residual macroscopic disease. Histopathology confirmed a well-differentiated PTC with features of tumour regression. In this case, TKI therapy in a locally advanced unresectable DTC reduced tumour size and infiltration to a degree that surgical resection of macroscopic disease was possible, without requiring airway resection. This raises the possibility that TKIs may have a neoadjuvant role in selected cases of locally advanced DTC to reduce tumour volume and therefore morbidity of subsequent surgical resection.

Not the same thing: metastatic PTCs have a different background than ATCs.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive form of thyroid cancer. By contrast, differentiated papillary thyroid cancer (PTC) only rarely behave aggressively and develop distant metastasis. Whether distantly metastatic PTC (DM-PTC) and ATC share a common genetic background is still to be defined. We used next-generation sequencing (NGS) to explore the genetic background of a cohort of ATC and DM-PTC and a group of well-differentiated PTCs that did not developed distant metastasis as control (ctrl-PTC). A panel of 128 amplicons within 21 thyroid cancer-related genes was analyzed in a set of 151 thyroid cancer samples including 66 ATCs and DM-PTCs. We showed that the ATC/DM-PTC group had an overall mutational load higher than ctrl-PTCs and that ATCs and DM-PTCs are characterized by a different genetic background, with the exception of mutations in the TERT promoter that were overrepresented in both ATCs (61.1%) and DM-PTCs (48.2%) vs non-aggressive ctrl-PTCs (7.6%). In ATCs, TERT promoter mutations were frequently associated with TP53 mutations, while in the DM-PTCs no significant co-occurrence was observed. No significant association of MED12 mutations with aggressiveness of thyroid cancer was observed in our analysis. Finally, correlation analysis showed that increasing number of mutations negatively impact on patient overall survival also within the ATC and DM-PTC group. In conclusions, overall our analysis further highlights the relevance of TERT promoter mutations in driving aggressiveness and provides new pieces of information in the definition of aggressiveness evolution of thyroid cancer lesions.

Abstract LB-182: Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer

Abstract Anaplastic thyroid cancer (ATC), contrary to well-differentiated papillary thyroid cancer (PTC), is one of the most aggressive human malignancies. Anaplastic thyroid cancer is responsible for more than half of all thyroid cancer deaths, with an overall mortality rate about 70% at 6 months and 81% at 12 months, despite only accounting for &amp;lt;2% of thyroid cancer incidence [1]. Both PTC and ATC are MAPK-driven cancers that have two mutually exclusive drivers with distinct signaling consequences: BRAF V600E mutation and RAS mutation [2-3]. In PTC, BRAF (V600E)-like tumors showed higher MAPK transcriptional output and lower expression of genes related with iodine metabolism, and RAS-like tumors showed lower MAPK signaling and comparatively higher expression of iodine metabolism genes. However, in ATC both BRAF mutant and RAS mutant tumors showed BRAF-like tumor transcriptional output. Down-regulation of Notch signaling by gamma-secretase inhibitor (GSI) or Notch1 RNAi reduced PTC cell proliferation [3]. Here by combining multiple gene expression microarray studies (TCGA, GSE27155, GSE29265 and GSE33630), we showed that compared with normal thyroid tissue the Notch signaling pathway was up-regulated in both PTC and ATC. However, ATC and PTC showed different activation patterns in terms of expression of Notch receptors, ligands and downstream targets. Compared with normal thyroid tissue, Notch1, Notch3 and JAG1 were up-regulated in both ATC and PTC, but were much higher in ATC. Compared with normal thyroid tissue, HEY1, HES4 and NRARP were up-regulated in both ATC and PTC. Comparing with PTC, HEY1 was also higher in ATC. However, HES1 was down-regulated in ATC but up-regulated in PTC. It was also reported that both Notch1 and Hes1 were up-regulated by activation of MAPK signaling in thyroid follicular cells with RET/PTC3 or BRAF (T1799A) [4]. Notch1 protein level was also higher in PTC [3]. All of the evidence above supports the hypothesis that Notch pathway may be a key signaling component along with aberrant activation of MAPK pathway in ATC. These data suggest inhibition of Notch signaling alone and/or combination with MAPK signaling inhibitors, such as BRAF inhibitor or ERK inhibitor, may be of benefit in ATC, and support investigation in a clinical trial. 1. Anaplastic Thyroid Carcinoma: Treatment Outcome and Prognostic Factors. Cancer 103 1330-1335,2015. 2. Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell 159, 676-690, 2014. 3. Notch Pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Translational oncology, 6,197-205, 2013. 4. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. JCI, 126, 1052-1066, 2016. Citation Format: Yan Ding, Hui-Rong Qian, Bharvin K R Patel, Gerald Joseph Oakley, Karim A. Benhadji, Emma Bowden, Amit Aggarwal. Notch signaling pathway is transcriptionally elevated in anaplastic thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-182.

PREDICTORS OF AGGRESSIVE DIFFERENTIATED THYROID CANCER. A REPORT OF A CASE OF PAPILLARY THYROID CANCER

Background. Differentiated thyroid cancer has a favorable prognosis in terms of relapse-free and overall survival. However, some cases of differentiated thyroid cancer (TC) are characterized by aggressive course with distant metastases and/or radioiodine refractoriness. Identification of histological subtypes of papillary thyroid cancer (PTC) and detection of specific mutations may have some prognostic value in the prediction of the disease course and clinical response to treatment. The severity of the disease depends on multiple clinical characteristics, morphological and molecular features of the tumor. Several histological variants of PTC with varying degrees of malignancy have been described so far: from well-differentiated PTC to radioiodine refractory undifferentiated anaplastic carcinoma with a high mitotic index and high probability of relapses. In this article, we present a case of PTC in a 76-year-old patient. The patient found a formation on the neck and complained of memory impairment. Upon examination, the patient was found to have a thyroid tumor with metastases in lungs, brain, and bones. The patient underwent thyroidectomy and started to receive suppressive doses of thyroxine. Stereotactic radiotherapy was performed to treat brain metastases. We observed a regression of small formations and partial response of larger metastatic foci. The patient received no radioiodine therapy due to his poor somatic status and extensive tumor spread. The patient received target therapy with sorafenib (800 mg/day) and bisphosphonates (BFT) for treatment of bone metastases. After the second cycle of target therapy, the dose of sorafenib was reduced by 50 % due to adverse events; during the next 10 month the patient received sorafenib at a dose of 400 mg/day. After the third cycle of target therapy we observed a stabilization of metastatic foci in the lungs and bones. However, during the treatment, the patient developed visceral metastases to the liver and the adrenal gland, a lytic metastasis in the right side of the mandible, and pain syndrome. A course of radiotherapy to the mandible was conducted along with BFT treatment. The patient received adequate analgesia and symptomatic therapy. The survival from the moment of diagnosis was 2 years. Results. We found that in some cases of differentiated TC, the disease has quite aggressive course with a rapid growth of the primary tumor and metastases into the brain and bones. Patients usually seek medical assistance at the advanced stages of the disease, when it is problematic to provide adequate therapy. The use of target therapy should be considered in such cases. There is a need to find new targets for the development of novel drugs for these patients. Conclusion . The most aggressive forms of PTC include diffuse sclerosing, tall cell, and insular variants of PTC. Various genetic abnormalities, such as BRAF mutation, can be detected in this case. The following clinical prognostic factors are used to determine metastatic potential, probability of relapse, and mortality: age under 15 years or over 45 years, male gender, family history of TC, and exposure to ionizing radiation. Thus, in some cases these markers can help to predict the course of TC and to provide adequate and timely treatment.

Prognostic value of vascular invasion in well-differentiated papillary thyroid carcinoma.

Vascular invasion (VI) is an important predictor of distant metastasis and possible radioactive iodine (RAI) benefit in follicular, Hürthle cell, and poorly differentiated thyroid carcinomas, but its role in well-differentiated papillary thyroid cancer (WDTC) remains unclear. Archived pathological material of all differentiated thyroid carcinoma patients undergoing primary surgical treatment at Memorial Sloan-Kettering Cancer Center between 1986 and 2003 was reviewed by two dedicated thyroid pathologists. Only WDTCs were included in the present study. Standard statistical methods were used to assess the relationship between VI and outcomes of interest, including 10-year disease-specific survival (DSS), regional recurrence-free survival (RRFS), and distant recurrence-free survival (DRFS). VI was present in 47 of 698 WDTC (6.7%). VI was significantly associated with tumor size >4.0 cm, extrathyroidal extension, distant metastasis, and RAI treatment. On univariate analysis, VI was predictive of decreased 10-year DRFS, but not DSS or RRFS. On multivariate analysis, VI was not an independent predictor of DRFS. Univariate survival analysis of 422 RAI-naïve WDTC showed that both size >4 cm and VI were predictors of outcome, but only size remained independently predictive on multivariate analysis. The presence of VI is not an independent predictor of outcome in WDTC.

The effect of surgeon experience on the detection of metastatic lymph nodes in the central compartment and the pathologic features of clinically unapparent metastatic lymph nodes: what are we missing when we don't perform a prophylactic dissection of central compartment lymph nodes in papillary thyroid cancer?

Prophylactic central neck dissection (PCND) for papillary thyroid cancer (PTC) is controversial. Recent publications suggest that the number and size of nodes and the presence of extranodal extension (ENE) are important features for risk stratification of lymph node metastases. We analyzed these features in clinically unapparent nodes that would not otherwise be removed. We also investigated the impact of surgeon experience on the ability to detect metastatic lymph nodes intraoperatively. Forty-seven patients with well-differentiated PTC, with no preoperative evidence of central metastases, were included in this study. Intraoperatively, clinically apparent disease was determined by inspection and palpation by the senior surgeon and a fellow/senior resident, and recorded in a blinded fashion. Rate of occult metastases based on intraoperative evaluation were tabulated for each group of surgeons. Histopathologic features of occult nodes were analyzed to determine what clinicians would be missing by foregoing a PCND, and how that would have impacted the patient management. The rate of occult metastases, based on senior surgeon assessment, was 26%, and did not differ significantly from fellow/senior resident assessment. The level of agreement between these two surgeon groups was moderate (k=0.665). Analysis of the false negative cases revealed that the size of the largest undetected node ranged from 0.1 to 1.3 cm; 36% of patients with occult metastases demonstrated five or more positive nodes, and 27% showed ENE. Clinical assessment based on intraoperative inspection and palpation had poor sensitivity and specificity in identifying metastatic central nodes, regardless of the level of experience of the surgeon. There was moderate agreement between surgeons of different experience levels. Sensitivity improved significantly with larger size of positive nodes, but not with the presence of multiple positive nodes or presence of ENE. In foregoing PCND in this patient population, our results suggest that treating clinicians miss potentially virulent disease with a large number of occult positive central nodes and occult nodes with ENE. This is the first report to address the pathologic features of clinically nonevident central nodes showing a high incidence of clinically relevant, adverse histologic features, as well as the impact of surgeon experience in performing the important intraoperative determination of whether there are clinically evident nodes that require removal.

Optimal Timing of Surgery for Differentiated Thyroid Cancer in Pregnant Women

Differentiated thyroid cancer (DTC) is the second most common cancer diagnosed in pregnant women, but there is no consensus as to whether surgery should be performed during pregnancy or after delivery. We retrospectively reviewed the records of 45 patients with DTC operated on during pregnancy or within 1year after delivery, and we compared the clinicopathological features and outcomes of the patients operated during pregnancy (group A, n=24) and the patients operated after delivery (group B, n=21). All 45 patients were histologically diagnosed with well-differentiated papillary thyroid cancer. Nineteen (79%) of the 24 patients in group A underwent thyroidectomy during the second trimester. No complications associated with surgery or general anesthesia were reported in either group. There were no significant differences between the two groups in terms of age, tumor size, incidence of lymph node metastasis, or incidence of extrathyroidal extension. No distant metastases were detected in any of the patients. Two small for date infants (8.3%) and 2 heavy for date infants (8.3%) were delivered in group A, but only 1 small for date infant (4.7%) was delivered in group B. There were no miscarriages, and none of the infants in either group had birth defects. Because 3 patients in group A and 1 patient in group B experienced a local recurrence, salvage surgeries were performed. Although thyroid surgery was performed safely in the second trimester, surgery after delivery was also acceptable. Surgery after delivery is recommended for most patients with non-aggressive DTC.

Is Above Age 45 Appropriate for Upstaging Well-Differentiated Papillary Thyroid Cancer?

ObjectiveAge greater than 45 years old is a prognostic marker in well-differentiated papillary thyroid cancer (PTC) using the American Joint Cancer Committee/Union Internationale Contre le Cancer Tumor Nodes Metastasis (AJCC/UICC TNM) staging system. Our clinical observation has been that patients aged 45 to 64 years have similar outcomes when compared to patients younger than 45 years, and we questioned the origin and accuracy of this prognostic variable. MethodsUsing SEERstat software, we analyzed the Surveillance, Epidemiology, and End Result (SEER) database for PTC using the following International Classification of Diseases for Oncology (ICD-O) codes: 8050, 8260, 8340, 8341, 8342, 8243, and 8344. Data were stratified in 5-year categories by age at diagnosis from 20 to 84 years old, with patients 85 years old and above categorized together. Survival is reported as cause specific. ResultsA total of 53,581 patients were identified. The 5-year survival rate decreased with each increasing age category with no inflection point at age 45 in the survival curve. While the prognosis was less favorable in each advancing age group, survival remained above 90% for all age groups under 65 years. ConclusionA review of the literature reveals a lack of data supporting the use of age 45 as a prognostic variable. Our SEER database review revealed a continuum of disease-specific mortality for each incremental 5-year time period above age 45. We conclude that the current use of age 45 as a single prognostic age marker does not accurately reflect the progressive mortality risk that is apparent with each 5-year increment in age. (Endocr Pract. 2013; 19:995-997)

Prophylactic neck dissection in papillary thyroid cancer: When is it necessary?

BACKGROUND The American Cancer Society estimates that there will be approximately 56,460 new diagnoses of thyroid cancer in the United States during 2012, and more than 90% will be papillary thyroid cancer (PTC). Despite the large, ever-increasing number of thyroid cancer cases, the ideal initial management of well-differentiated PTC remains controversial. The role of the prophylactic central neck dissection (pCND) has emerged as the most highly debated topic, with conflicting reports regarding indications, recurrence prevention, and reduction of cause-specific mortality. Currently, there is no argument that a formal, compartmental CND should be performed if preoperative or palpable nodal disease is encountered. However, the 2009 American Thyroid Association (ATA) guidelines state that, “Prophylactic central compartment neck dissection may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4; Grade C recommendation; expert opinion).” With the advent of personalized therapy based on molecular testing, the BRAF gene has shown the most promise in predicting lymph node metastases and may be used to direct clinicians on whether to perform a pCND. The focus of the review will seek to answer the question of best practice with regards to pCND in PTC. LITERATURE REVIEW Due to the excellent outcomes seen with PTC, the importance of lymph node metastases has been difficult to interpret. Recent, large, population-based studies have demonstrated a decrease in cause-specific survival in lymph-node positive PTC patients. Zaydfudim et al. used the Surveillance, Epidemiology, and End Results database to analyze outcomes of 30,054 patients with PTC. They concluded through multivariate analysis that metastatic LNs conveyed a 46% increased risk of death (HR, 1.46; P<.001) in patients 45 years, even with the majority of patients with excellent long-term survival. However, in patients< 45, lymph node status did not influence survival. While the presence of metastatic positive lymph nodes in PTC may dictate a decrease in cause-specific survival, does performing a prophylactic central neck dissection actually improve the patient’s outcome? A meta-analysis of five studies with a total of 1,264 patients demonstrated a decrease in lymph node recurrence (2% vs. 3.9%) in the thyroidectomy1pCND group, but this did not achieve statistical significance. The rate of transient recurrent laryngeal nerve paralysis (1.8%–5.4% thyroidectomy1pCND, 1%–1.3% thyroidectomy alone) and transient hypoparathyroidism (18%– 44% thyroidectomy1pCND, 8%–14% thyroidectomy alone (P< 0.02)) was higher in the group receiving pCND. Permanent recurrent nerve paralysis and hypocalcemia were not different between the two arms. The authors concluded that the balance between the risks and benefits favored thyroidectomy alone. However, they recognized several limitations to the study: inclusion of retrospective data, inconsistencies in the use of RAI and thyroid suppression postoperatively, limited data on timing of recurrence, and a lack of standardized reporting with regard to the extent of central neck dissection (ipsilateral vs. bilateral, etc.). The authors conclude with the call for a large, prospective trial to fully resolve the controversy. However, the feasibility of such a randomized trial was investigated by the ATA, which concluded that prohibitively large sample sizes (5,840 patients) and approximately $20 million would be required to demonstrate significant differences in outcomes. From the Louisiana State University Health Sciences Center– Shreveport, Department of Otolaryngology/Head and Neck Surgery, Shreveport, Louisiana, U.S.A.

Differential proteomic and phenotypic behaviour of papillary and anaplastic thyroid cell lines

Thyroid carcinomas account for a minority of all malignant tumours but, after those of the gonads, they represent the most common forms of endocrine cancers. They include several types, among which the papillary thyroid cancer (PTC) and the anaplastic thyroid cancer (ATC) are the best known. The two hystotypes display significant biological and clinical differences: PTC is a well differentiated form of tumour with a high incidence and a good prognosis, while the ATC is less frequent but represents one of the most aggressive endocrine tumours with morphological features of an undifferentiated type. To date, as far as we know, no conclusive studies, useful to design arrays of molecular markers, have been published illustrating the phenotypic and proteomic differences between these two tumours. The aim of this work was to perform a comparative analysis of two thyroid cancer cell lines, derived respectively from papillary (BCPAP) and anaplastic (8505C) thyroid carcinomas. The comparative analysis included cell behaviour assays and proteomic analysis by 2D-PAGE and mass spectrometry. The results have highlighted a new proteomic signature for the anaplastic carcinoma-derived cells, consistent with their high proliferation rate, motility propensity and metabolic shift, in relation to the well-differentiated PTC cells.

Undetectable thyroglobulin after total thyroidectomy in patients with low- and intermediate-risk papillary thyroid cancer— is there a need for radioactive iodine therapy?

The efficacy of radioactive iodine therapy (RAI) in patients who have an undetectable thyroglobulin (Tg) level after total thyroidectomy in well-differentiated papillary thyroid cancer (PTC) is questionable. The objectives of this study were to report the risk of recurrence in patients with PTC who had an undetectable Tg level after total thyroidectomy managed with postoperative RAI and without RAI. After approval by the institutional review board, 751 consecutive patients who had total thyroidectomy for PTC as well as postoperative Tg measurement were identified from our institutional database of 1163 patients treated for well-differentiated thyroid carcinoma at Memorial Sloan Kettering Cancer Center between 1999 and 2005. Of these, 424 patients had an undetectable postoperative Tg (defined as a Tg <1 ng/mL) of whom 80 were classified as low, 218 intermediate, and 126 high risk via use of the GAMES (grade, age, distant metastasis, extrathyroidal extension, and size of the neoplasm) criteria. Patient, neoplasm, and treatment characteristics were recorded on the low- and intermediate-risk patients. Recurrence was defined as any structural abnormality on examination or imaging and confirmed by fine-needle aspiration biopsy. Disease-specific survival and recurrence-free survival (RFS) were calculated with the Kaplan-Meier method. Univariate analysis was carried out by the log rank test and multivariate analysis by Cox proportional hazards method. In the low-risk group (n = 80), 35 patients received postoperative RAI and 45 did not. Comparison of patient and tumor characteristics showed patients treated without RAI were more likely to have T1 tumors (82% vs 60%, P = .027). There were no disease-specific deaths in either group. There was 1 neck recurrence in the group that did not receive RAI. Patients managed without RAI had a similar RFS to patients managed with RAI (96% vs 100%, P = .337). In the intermediate risk group (n = 218), 135 were managed with RAI and 83 without. Comparison of patient and tumor characteristics showed patients managed without RAI were more likely to be older patients (≥ 45 years: 90% vs 39%, P < .0005) with smaller tumors (pT1T2: 97% vs 62%, P < .0005) and negative neck disease (N0: 56% vs 30%, P < .0005). There were no disease specific deaths in either group. There were 7 recurrences, of which 6 were in the RAI cohort (5 regional, 1 distant) and 1 in the non-RAI cohort (1 regional). Patients managed without RAI had a similar RFS to patients managed with RAI (97% vs 96%, P = .234). Select low- and intermediate-risk group patients who have undetectable Tg after total thyroidectomy for PTC can be managed safely without adjuvant RAI with no increase in risk of recurrence.

Multifocal Micropapillary Thyroid Cancer: A New Indication for Total Thyroidectomy?

American Thyroid Association guidelines recommend total thyroidectomy (TT) for thyroid cancers 1 cm or greater. Liberal use of neck sonography has resulted in an increased incidence of papillary cancers detected at earlier stages with approximately half at the micropapillary level and occasionally multifocal. Concerns regarding the safety of routine TT, especially in young patients with favorable cancers, and the clinical significance of detected multifocal micropapillary cancers have been raised. Records of 516 consecutively treated patients with thyroid cancer were reviewed. A subset of 269 cases with well-differentiated papillary thyroid cancer (WDPTC) confined within the capsule of the involved lobe undergoing TT was analyzed. Patients were stratified according to age, tumor size, evidence of ipsilateral multifocality, and presence or absence of contralateral nonpalpable malignancy. Overall contralateral histologic malignancy was demonstrated in 46.4 per cent (125 of 269). The incidence was 34 per cent (30 of 88) of subcentimeter (less than 1 cm) tumors and significantly increased to 52 per cent (95 of 181) in tumors 1 cm or greater (P = 0.006). This incidence significantly approached 76 per cent (13 of 17) in subcentimeter but multifocal tumors when 45 years or older (P = 0002). One patient developed permanent hypocalcemia (0.4%). There were no recurrent nerve injuries. The incidence of bilateral cancer was significant in 1-cm or greater WDPTC. Patients with subcentimeter multifocal tumors, when older than 45 years, were even at higher risk for bilateral cancer. Because TT is advocated for patients with WDPTC 1 cm or greater, it should also be considered in those older than 45 years with ipsilateral multifocal micropapillary cancers, because it can be performed safely.

BRAF V600E mutation does not predict recurrence after long‐term follow‐up in TNM stage I or II papillary thyroid carcinoma patients

The BRAF V600E mutation may serve as a marker of disease recurrence in well-differentiated papillary thyroid cancer (PTC). Our aim was to study if TNM stage I or II PTC patients, with and without recurrence after long-term follow-up would differ in BRAF status. BRAF status was retrospectively determined in tumour tissue from a cohort of low-risk PTC patients (n = 461) with and without recurrence after 16 years of follow-up. Initial treatment was total thyroidectomy (TTE) and radioiodine remnant ablation (RRA). Forty-six patients (9.9%) experienced disease recurrence. BRAF mutation was positive in 66% (17/26) of patients with and 68% (17/25) without recurrence (p = NS). Fifty per cent of BRAF positive and 53% of BRAF negative patients experienced disease recurrence (p = NS). Time to recurrence was 52 (range 18-144) and 36 (range 16-71) months, respectively (p = NS). Primary tumour size, nodal metastasis and local infiltration at presentation did not differ between BRAF positive and negative patients (2.0 vs 2.2 cm, 21% vs 35% and 6% vs 12%, respectively, all p = NS). Taken together, BRAF V600E is common in Finnish patients with low-risk PTC but does not predict recurrence after long-term follow-up after initial treatment with TTE and RRA.

Psychological impact of thyroid surgery on patients with well-differentiated papillary thyroid cancer

Most patients with well-differentiated thyroid cancer (WDTC) have favorable prognosis and survive for many years. We investigated the effect of thyroid cancer surgery on subsequent psychological aspects. Demographic parameters, clinical characteristics, and other data were obtained from self-administered questionnaires administered to WDTC patients at various times after thyroid cancer surgery. The questionnaires assessed psychological aspects based on three scales: a performance of everyday activities questionnaire developed for this study, the Hospital Anxiety and Depression Scale (HADS), and the Fear of Progression Questionnaire (FoP-Q). The mean time since thyroid surgery and the survey was 3.5years. More than half of the patients (60.7%) were able to perform all activities without limitations. The HADS scores indicated no anxiety or depression in most patients, and the FoP-Q scores indicated little fear of cancer progression. The time since surgery, type of surgery, use of postoperative radioiodine ablative therapy, and recurrence or metastasis had no significant effect on the psychological scores. Our study indicates that most WDTC patients are psychologically stable after the thyroid cancer surgery.