nan GanlyIan

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.

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.

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.

Multi-Organ Distant Metastases Confer Worse Disease-Specific Survival in Differentiated Thyroid Cancer

BACKGROUND Differentiated thyroid cancer (DTC) is usually associated with an excellent prognosis. With appropriate management of disease in the neck, death from thyroid cancer is more commonly related to the impact of distant metastases rather than locoregional recurrence. However, many patients with distant metastases can have very long periods of progression-free survival. The aims of this study were to determine the impact of single and multi-organ distant metastases (SODM and MODM) on survival, and identify factors that predict SODM progressing to MODM. METHODS An institutional database of 3664 previously untreated patients with DTC who had surgery between 1986 and 2010 was reviewed. One hundred and twenty-five (3.4%) patients developed distant metastases, of whom 93 developed SODM and 32 MODM. Overall survival was determined for each group by the Kaplan-Meier method. Factors predictive of MODM were identified by univariate and multivariate analysis. Multi-organ recurrence-free survival (MORFS) is a measure of SODM progressing to MODM disease. MORFS was calculated from the time of first distant metastasis to the time of second organ involvement by distant metastases. RESULTS The median age was 56 years (range 5-86 years). The median follow-up was 77 and 79 months (range 2-318 months) for the SODM and MODM groups respectively. SODM patients had five-year survival of 77.6% from the time of first distant metastasis, whereas MODM patients had a significantly poorer survival of just 15.3% from the time of second organ distant metastasis to death (p<0.001). The median time from first to second distant metastasis was 14.7 months (range 1-121 months). Seventy-one (57%) patients had M1 disease at presentation. Being aged ≥ 45 years (p = 0.05) and having an unstimulated serum thyroglobulin (Tg) level of ≥ 30 ng/mL at the time of diagnosis of initial distant metastasis (p<0.001) were univariate predictors of developing MODM. Controlling for age, an unstimulated serum Tg level of ≥ 30 ng/mL conferred a hazard ratio of 5.77 ([CI 2.13-15.64]; p = 0.001) for diagnosis of MODM. CONCLUSIONS MODM are associated with a poorer survival compared to patients with SODM. A serum Tg level >30 ng/mL at the time of first distant metastases confers more than a fivefold risk of having MODM identified during follow-up.

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

BACKGROUND 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. METHODS 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). RESULTS 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. CONCLUSION The presence of VI is not an independent predictor of outcome in WDTC.

Using the American Thyroid Association Risk-Stratification System to Refine and Individualize the American Joint Committee on Cancer Eighth Edition Disease-Specific Survival Estimates in Differentiated Thyroid Cancer

BACKGROUND The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has reclassified up to one third of differentiated thyroid cancer patients into one of the younger prognostic stage groups (<55 years of age at diagnosis, stage I or stage II). This reclassification widens the spectrum of disease in these lower stages without significantly impacting overall disease-specific survival (DSS) for the entire stage group. However, the optimistic DSS estimates in the <55-year-old stage groups may not accurately reflect the prognosis of individual patients with American Thyroid Association (ATA) high-risk features. Therefore, the aim of this study was to integrate the ATA risk classification system into the eighth edition AJCC staging system to refine and individualize DSS estimates for differentiated thyroid cancer patients aged <55 years at diagnosis. METHODS Using the Memorial Sloan Kettering Cancer Center tumor registry, 4881 adult DTC patients aged <55 years at diagnosis receiving initial therapy between 1980 and 2016 were retrospectively analyzed. Using Memorial Sloan Kettering Cancer Center registry coded data, all patients were assigned an eighth edition AJCC stage (I or II), ATA risk of recurrence (low, intermediate, or high), and age group at diagnosis (younger patients defined as ≤45 years old, older patients defined as 45-55 years old). The primary outcome was 10-year DSS. RESULTS A total of 122 (2.5%) disease-related deaths were observed in the cohort of 4881 patients during a median follow-up of 6.6 years. Integration of the AJCC stage, ATA risk, and age groups identified six subgroups with differing outcomes: (i) stage I/ATA low risk, younger and older, 100% DSS; (ii) stage I/ATA intermediate risk, younger and older, 98% DSS; (iii) stage I/ATA high risk, younger, 95% DSS; (iv) stage I/ATA high risk, older, 89% DSS; (v) stage II/ATA high risk, younger, 78% DSS; and (vi) stage II/ATA high risk, older, 61% DSS. CONCLUSIONS Integration of AJCC stage, ATA risk, and age group (i) identifies six subgroups of patients with progressively worse DSS as AJCC stage, ATA risk, and age increases, and (ii) provides a more individualized estimate of DSS, especially in ATA high-risk patients.

Previous external beam radiation treatment exposure does not confer worse outcome for patients with differentiated thyroid cancer

BACKGROUND Radiation exposure, especially in childhood, is known to increase the risk for the development of thyroid cancer. However, the prognosis of patients with thyroid cancer with a history of radiation treatment exposure remains unclear. METHODS One hundred and sixteen patients with a previous history of radiotherapy in the head and neck region were identified from an institutional database of 3664 patients with differentiated thyroid cancer treated between 1986 and 2010. Using the Kaplan-Meier method, disease-specific survival and recurrence-free survival were compared between patients with (RT; n = 116) and without (No RT; n = 3509) a prior history of radiation exposure. RESULTS The median ages of the RT and No RT cohorts were 52 and 47 years. The median follow-up for both groups was 54 months. Patients who had a prior history of radiation treatment exposure were more likely to be male (38.8% vs. 26.9%; p = 0.005) and older than 45 years of age (67.2% vs. 53.9%; p = 0.005). Other patient, tumor, and treatment characteristics were similar between the groups. There was no difference in the five-year disease-specific survival of the RT and No RT patients (97.4% vs. 98.7%; p = 0.798). The five-year recurrence-free survival was also similar between the RT and No RT patients (97.8% vs. 94.9%; p = 0.371). CONCLUSION The findings suggest that differentiated thyroid cancer patients with a history of prior radiation treatment exposure have similar outcomes to those with no history of head and neck radiation exposure.