TuttleR. Michael

Thyrotropin Suppression Increases the Risk of Osteoporosis Without Decreasing Recurrence in ATA Low- and Intermediate-Risk Patients with Differentiated Thyroid Carcinoma

BACKGROUND Levothyroxine suppression of thyrotropin (TSH) is broadly applied to patients with thyroid cancer despite lack of consensus on the optimal TSH concentration necessary to reduce cancer recurrence while minimizing toxicity from subclinical hyperthyroidism. The objectives of this study were to examine the beneficial effects and the cardiac and skeletal toxicity of TSH suppression in well-differentiated thyroid carcinoma (DTC). METHODS A total of 771 patients (569 women) at ATA low or intermediate risk of recurrence, with a mean age of 48±14 years, and undergoing total thyroidectomy at a tertiary care center between 2000 and 2006 were followed for a median of six and a half years. They were divided into a suppressed TSH group (median TSH ≤0.4 mIU/L) and a nonsuppressed group (median TSH >0.4 mIU/L). Structural recurrence of thyroid cancer, postoperative atrial fibrillation (AF), and osteoporosis were examined in the two groups. Osteoporosis was only examined in women. RESULTS A total of 43/771 (5.6%) patients recurred, 29/739 (3.9%) patients were diagnosed with postoperative osteoporosis, and 17/756 (2.3 %) were diagnosed with postoperative AF. Despite similar rates of recurrence (HR 1.02, p=0.956 [CI 0.54-1.91]), patients treated to a median TSH ≤0.4 mIU/L were at increased postoperative risk of a composite outcome of AF and osteoporosis (HR 2.1, p=0.05 [CI 1.001-4.3]) compared to those not suppressed. A differential risk of AF alone (HR 0.78, p=0.63 [CI 0.3-2.1]) was not detected, but postoperative osteoporosis was increased among women with a suppressed TSH compared to those not suppressed (HR 3.5, p=0.023 [CI 1.2-10.2]). The increased risk of postoperative osteoporosis disappeared when the patients median TSH was maintained around 1 mIU/L. CONCLUSION TSH suppression significantly increases the risk of postoperative osteoporosis without changing tumor recurrence in ATA low- and intermediate-risk patients with DTC. Future interventions should focus on avoiding harm in indolent disease.

Prognostic Implications of Papillary Thyroid Carcinoma with Tall-Cell Features

BACKGROUND The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall-cell features are unknown. METHODS All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC cases were defined as having <30% tall cells, PTC with tall-cell features (PTC TCF) as 30%-49% tall cells, and tall-cell variant of PTC (TCV) as ≥ 50% tall cells. All classical PTC, PTC TCF, and TCV ≥ 1 cm in size were included. RESULTS A total of 453 patients satisfied the inclusion criteria (288 classical PTC, 31 PTC TCF, and 134 TCV). Classical PTC patients were younger than their PTC TCF and TCV counterparts (p<0.0002). There was an increase in tumor size from classical PTC to PTC TCF and TCV (p=0.05). Extensive extrathyroid extension and positive margins were more often present in TCV and PTC TCF than in classical PTC (p=0.0001 and p=0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in classical PTC (p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered in TCV patients than in their PTC TCF and classical PTC counterparts (p=0.001 and p=0.0001 respectively). Median follow-up was 9.3 years. Ten-year disease-specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in classical PTC (100%; p<0.001). Ten-year distant recurrence-free survival (RFS) was higher in classical PTC (98%) than in PTC TCF (89%) and TCV (96%; p=0.03). In multivariate analysis, the presence of more than five positive nodes and extranodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence, while none of the 288 classical PTC transformed into higher grades (p=0.017). CONCLUSIONS PTC TCF and TCV have similar clinicopathologic features that are more aggressive than classical PTC. PTC TCF and TCV have similar DSS and distant RFS but poorer outcomes than classical PTC. PTC TCF are currently being treated like classical PTC, that is, less aggressively than TCV. PTC TCF and TCV TCV have a higher rates of high-grade transformation than classical PTC. Consideration should be given to using a 30% tall-cell threshold to diagnose TCV.

Prognostic Factors in Papillary Microcarcinoma with Emphasis on Histologic Subtyping: A Clinicopathologic Study of 148 Cases

BACKGROUND There continues to be controversy regarding which clinicopathological features confer a higher risk of adverse outcome in papillary microcarcinomas (PMC). The aim of this study was to assess the prognostic value of a meticulous histologic examination in PMC. METHOD All papillary thyroid carcinoma <1 cm in size without associated larger thyroid carcinomas, identified between 1977 and 2002, were categorized as PMC and subjected to a meticulous histopathologic examination by 2 thyroid pathologists. RESULTS 148 PMC patients fulfilled the inclusion criteria. Within PMC, young age, male sex, tumor multicentricity, extrathyroidal extension, and infiltrative and larger tumor (≥0.5 cm) correlated with the presence of >1 cm metastatic node (MN) or >3 MN at presentation (p<0.05). With a median follow-up of 9.9 years, only 1 (0.7%) of 134 PMC patients died of thyroid carcinomas and 3 (2.2%) had recurrences in the neck. The patient who died had harbored a poorly differentiated carcinoma in his MN. The presence of MN and especially a large MN (>1 cm) correlated with worse recurrence-free survival (p=0.005 and p<0.0001, respectively). Except for one, all individuals with clinically adverse outcomes had >1 cm MN. Patients whose MNs were predominantly composed of poorly differentiated carcinoma or tall cell variant papillary thyroid carcinoma had a significant shorter recurrence-free survival (p<0.0001). Only 1 of 80 radioactive iodine-naïve PMC patients with absent or small MN (≤1 cm) had recurrence with a median follow-up of 9.2 years. CONCLUSIONS (i) The size and histotype of the MN are predictors of outcome in PMC and should be recorded. (ii) The very rare PMC patients who suffer recurrence or even die of disease have usually aggressive histopathologic features at presentation. (iii) PMC patients with nodal disease that is small or absent at presentation are at a very low risk of recurrence and may be spared radioactive iodine therapy.

Response to Initial Therapy Predicts Clinical Outcomes in Medullary Thyroid Cancer

BACKGROUND Risk stratification in medullary thyroid cancer (MTC) has traditionally relied on standardized anatomic staging systems that, despite providing valuable prognostic information, do not adequately predict the risk of persistent or recurrent disease. As dynamic risk stratification has been demonstrated to be clinically valuable in nonmedullary thyroid cancer, we adapted our response to therapy definitions in order to apply them to MTC. In this study, we evaluate and compare the clinical utility of our previously proposed MTC response to therapy stratification with a traditional standardized anatomic staging system. METHODS Both the Tumor, Node, Metastasis/American Joint Cancer Committee (TNM/AJCC) staging system and our previously proposed response to initial therapy staging system was evaluated in 287 MTC patients followed for a median of five years. RESULTS The TNM/AJCC staging system provided adequate risk stratification with regard to disease-specific mortality and the likelihood of having no evidence of disease at final follow-up, but did not adequately stratify patients with regard to the likelihood of having structural persistent disease, biochemical persistent disease, or recurrence. However, the response to initial therapy risk stratification system provided clinically useful risk stratification with regard to disease-specific mortality, the likelihood of having no evidence of disease at final follow-up, the likelihood of having a biochemical persistent disease at final follow-up, and the likelihood of having structural persistent disease at final follow-up. Furthermore, the response to therapy risk stratification system demonstrated a higher proportion of variance explained (54.3%) than the TNM/AJCC system (23.9%). CONCLUSION Our data demonstrate that a dynamic risk stratification system that uses response to therapy variables to adjust risk estimates over time provides more useful clinical prognostic information than static initial anatomic staging in MTC thyroid cancer.

Higher Administered Activities of Radioactive Iodine Are Associated with Less Structural Persistent Response in Older, but Not Younger, Papillary Thyroid Cancer Patients with Lateral Neck Lymph Node Metastases

BACKGROUND While radioactive iodine (RAI) adjuvant therapy is commonly recommended for most papillary thyroid cancer patients presenting with large volume nodal involvement, it remains unclear if such therapy impacts the disease-specific recurrence rate and overall survival. In this study, we compared the risk of achieving a structural persistent response after low administered activity (100 mCi), intermediate administered activity (150 mCi), and high administered activity (>200 mCi) RAI adjuvant therapy in patients presenting with pathologic N1b disease. METHODS This was a retrospective review of 181 papillary thyroid cancer patients with N1b disease treated with total thyroidectomy, neck dissection, and RAI remnant ablation. Dose-response relationships were determined between the administered activity of (131)I and the best response to initial therapy. RESULTS Out of the 181 patients, only 39% achieved no clinical evidence of disease (NED) after initial therapy. Young patients (Stage I) had a statistically nonsignificant trend toward higher rates of NED with increasing dose (34% low activity, 36% intermediate activity, 46% high activity), but there was no evidence of dose-response effect with regard to the likelihood of having a structural persistent response to initial therapy or the likelihood of having persistent biochemical evidence of disease. However, analysis of the older patients (Stage IVa) did reveal a trend toward statistically significant dose-response relationships with increasing administered activities being associated with lower rates of structural persistent response (46% low activity, 23% intermediate activity, 17% high dose). Unfortunately, the lower rate of structural persistent response only modestly increased the likelihood that patients would be NED but was instead associated with a higher proportion of patients being classified as having biochemical persistent disease at 12-18 months. CONCLUSIONS It appears that administering more than 100 mCi of RAI as adjuvant therapy in N1b disease is unlikely to improve the initial response to therapy. This is especially true for the younger (Stage I) patients. It is plausible that administered activities of 150-260 mCi may be associated with an improved response to initial therapy in older patients (Stage IVa) who are probably at highest risk of having poor outcomes, but the potential benefit from RAI should be balanced against potential adverse effects in those patients.

Time Course and Predictors of Structural Disease Progression in Pulmonary Metastases Arising from Follicular Cell–Derived Thyroid Cancer

BACKGROUND With the advent of molecular targeted therapy for the management of radioactive iodine (RAI) refractory, progressive metastatic thyroid cancer, it becomes important to define the time course and risk factors for structural disease progression in follicular cell-derived thyroid cancer (FCDTC) patients. This will help in defining the optimal time to start these therapies and better define their impact on structural disease progression. OBJECTIVES This retrospective review of 199 consecutive patients with FCDTC presenting with lung metastasis examined the progression-free survival (PFS) in thyroid cancer patients with lung metastasis treated with surgery and RAI, and who had not received molecular targeted therapy or chemotherapy. RESULTS The median overall survival (OS) was 10.45 years, while the median PFS was 3.65 years. A strong correlation was found between OS and PFS. PFS is shorter in patients with RAI refractory disease, poorly differentiated/Hürthle cell histologies, male sex, fluorodeoxyglucose-avid metastatic foci, older age (>45 years), and pulmonary metastases >1 cm. At final follow-up (a median of 6.9 years from lung metastasis diagnosis), 68% of the patients had progressed and 46% had died. CONCLUSIONS With the exception of younger patients with low disease burden, most patients presenting with lung metastasis from FCDTC (RAI avid and RAI refractory) using standard-of-care approaches will have disease progression on long-term follow-up. Additional studies are needed to identify novel therapies that would improve the PFS of such patients.

Central Lymph Node Characteristics Predictive of Outcome in Patients with Differentiated Thyroid Cancer

BACKGROUND The aim of our study was to determine central compartment lymph node (LN) characteristics predictive of outcomes in patients with differentiated thyroid cancer (DTC) and pathologically confirmed positive central LNs, in the absence of lateral neck disease or distant metastases at presentation. METHODS An institutional database of 3664 previously untreated patients with DTC operated between 1986 and 2010 was reviewed. Six hundred patients with central compartment nodal disease on histopathology were identified. Patient demographics, number of positive LNs, size of largest LN, and presence of extranodal spread (ENS) were recorded for each patient. Variables predictive of recurrence-free survival (RFS) were identified using the Kaplan-Meier method. Univariate analysis was carried out by the log-rank test and multivariable analysis was carried out using cox proportional hazard model. RESULTS The median age of the cohort was 41 years (range 12-91 years). The median follow-up was 61 months (range 1-330 months). Neck recurrence occurred in 43 patients. Recurrence occurred in the central neck in 11 patients, lateral neck in 27 patients, and both compartments in five patients. Factors predictive of neck RFS on univariate analysis were higher T stage (p=0.007), increased number of positive LNs, increased LN diameter, and presence of ENS (p=0.001). Multivariable analysis of LN characteristics showed that the only statistically significant predictor of neck recurrence was the presence of ENS. Neck RFS at five years for patients with and without ENS was 84.7% and 94.5% respectively (p=0.001). CONCLUSION The LN feature most predictive of neck recurrence appears to be the presence of ENS in the positive central neck.

Observing Micopapillary Thyroid Cancers

M icropapillary thyroid carcinoma (MPC) is extraordinarily prevalent in the population. Autopsy studies demonstrate an MPC prevalence of 25–35% in Finland and Japan; 10–15% in Canada, Poland, and Colombia; and 5–13% in the United States in adults dying of unrelated causes (1–6). Interestingly, neither the size of the MPC nor the likelihood of finding MPC at autopsy in adults is related to age or sex (2,3,6–11). Until recently, such cancers were considered occult, but high-resolution imaging and aggressive use of fine-needle aspiration have resulted in an epidemic of these small tumors. In the 1960s, only 5% of thyroid surgery was being done for MPC; this increased to 22% by the 1990s (12), and is now approaching 50% of thyroid surgeries at some centers (13–15). And yet, this represents only the tip of the iceberg. If we use 6% as a conservative estimate of the prevalence of MPC in the United States, one would predict over 18 million patients with disease. Yet, the SEER database reports a U.S. prevalence of only half a million cases of all types and sizes of thyroid cancer (http://seer.cancer.gov/statfacts/html/thyro.html). Thus, to date, we have identified less than 3% of the patients with these small tumors. Unless we change our approach to this disease, papillary cancer will continue to be one of the fastest growing malignancies worldwide for many more years.

Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics

BACKGROUND Distant metastases (DM) are a rare occurrence in well-differentiated thyroid carcinoma. The aim of this study was to analyze the clinical, pathologic, and molecular features of primary thyroid carcinoma with low-risk histology that develop DM. METHODS A detailed clinicopathologic review and targeted next-generation sequencing were performed on a cohort of well-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion, or significant lymph node metastases but exhibiting DM. RESULTS Primary well-differentiated thyroid carcinoma with low-risk histologic features and DM was a rare occurrence, accounting for only 3% of metastatic non-anaplastic thyroid carcinoma. All 15 cases meeting the inclusion criteria harbored DM at presentation. The majority (11/15) of these tumors were follicular variant of papillary thyroid carcinoma (PTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated Hürthle cell carcinoma (n = 2), encapsulated follicular carcinoma (n = 1), and an encapsulated papillary carcinoma classical variant (n = 1). Of the 12 encapsulated carcinomas, 10 had capsular invasion only and no vascular invasion. Ninety-two percent of the tumors exhibited extensive intra-tumoral fibrosis. Among the eight tumors that were subjected to next-generation sequencing analysis, a RAS mutation was the main driver (5/8), and TERT promoter mutation was highly prevalent (6/8). In four cases, TERT promoter mutations were associated with RAS or BRAF mutations. BRAF-mutated classical variant of papillary carcinoma also presented with DM but was less common (1/8). In 11/15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3/4 incidental cases that were genotyped, TERT promoter mutations were found. CONCLUSIONS When DM occur in primary thyroid carcinoma with low-risk histology, they are almost always found at presentation. The majority are encapsulated follicular variant of PTC with capsular invasion only. TERT promoter mutations occur at a higher rate than that seen in PTC in general and may help explain the aggressive behavior of these histologically deceptive primary carcinomas.

Implementing the Modified 2009 American Thyroid Association Risk Stratification System in Thyroid Cancer Patients with Low and Intermediate Risk of Recurrence

OBJECTIVE The primary purpose of this study was to validate the proposed modified 2009 American Thyroid Association Risk Stratification System (M-2009-RSS) in patients with thyroid cancer and to compare the findings with those of the 2009 ATA Risk of Recurrence (2009 ATA-RR) and the Ongoing Risk of recurrence system. The secondary purpose was to assess which risk stratification system had the best predictive value to foresee the probability of structural incomplete response or the no evidence of disease (NED) status at the end of follow-up. SUBJECTS AND METHODS This retrospective review included 149 patients with differentiated thyroid cancer who had low and intermediate 2009 ATA-RR and were treated at a single experienced center and followed-up for a median of 6 years (range 3-12 years). Each patient was risk stratified using both the 2009 ATA-RR and the M-2009-RSS. The primary endpoints were 1) the best response to initial therapy defined as either excellent response, biochemical or structural incomplete response, or indeterminate response; 2) clinical status at final follow-up defined as either NED, biochemical incomplete response, structural incomplete response, indeterminate response, or recurrence (biochemical or structural disease identified after a period of NED), and 3) ongoing RR defined as low or high risk according several outcomes after initial treatment. RESULTS Mean age of included patients was 45.3±13 years. Both the ATA 2009-RR and the M-2009-RSS provided clinically meaningful graded estimates with regard to the status of NED at the end of follow-up in low-risk patients (84% for 2009 ATA-RR and 74% for M-2009-RSS) or the likelihood of having persistent structural disease (0% for 2009 ATA RR and 3.6% for the M-2009-RSS). When patients were classified as low risk, the positive predictive value (PPV) and negative predictive value (NPV) to predict structural disease was 0% and 88.7% for the 2009 ATA-RR, 3.6% and 86.5% for the M-2009-RSS, and 1.6% and 68.2% for the ongoing RR (p=0.022 and 0.055 of chi-square test for PPV and NPV, respectively). CONCLUSIONS Despite expanding the definition of low risk to include small-volume lymph node metastases, minor extrathyroidal extension, and minimally invasive follicular thyroid cancer, the M-2009-RSS predicts clinical outcomes (structural incomplete response and NED at the end of follow-up) that are very similar to the previously validated 2009 ATA RR classification system.