Should Total Thyroidectomy Be Recommended for Patients with Familial Non-medullary Thyroid Cancer?

BACKGROUND: It is unknown whether familial non-medullary thyroid cancer (FNMTC) has more aggressive clinical features and a worse prognosis than sporadic non-medullary thyroid cancer (SNMTC). METHODS: We retrospectively reviewed 2894 patients with differentiated thyroid cancer who underwent primary thyroidectomy, identified 391 FNMTC cases, and compared the prevalence, surgical extension, and clinicopathologic features of FNMTC and SNMTC. RESULTS: A family history of thyroid cancer was noted in 391 patients (13.5%), with 85% having two affected relatives and 15% with ≥3 affected relatives. A sibling was affected in 52.9% of cases, and in 47.1%, both parent and child were affected. There were no significant between-group differences in sex, age, tumor size, extrathyroidal extension, or central lymph node metastases. Significantly more patients with FNMTC exhibited multifocal disease (p = 0.020) or benign nodules (p = 0.015). Lateral neck lymph node metastases were noted in 6.6% (SNMTC) and 9.7% (FNMTC, p = 0.021) of patients. Multifocality and combined benign masses were more frequently observed in patients with FNMTC in multivariate analysis. In the FNMTC group, seven experienced disease recurrence, with no mortality noted during follow-up. CONCLUSIONS: FNMTC is not more aggressive than SNMTC; however, FNMTC should be treated with total thyroidectomy because of the increased disease multifocality and the presence of benign nodules. Lateral neck lymph node metastases were more likely in patients with FNMTC, although we could not estimate prognosis. All patients with thyroid cancer should be checked for family disease history and undergo preoperative ultrasonography to determine the extent of node dissection and the need for total thyroidectomy.

Spindle epithelial tumor with thymus-like differentiation of the thyroid in a 70-year-old man.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland mostly occurring in young patients. The imaging findings of SETTLE tumors are yet to be defined. However, they are usually described as well-defined heterogeneously enhanced masses on CT scan. The current case has the potential growth as compared with a 2009 chest radiography. We took into account the possibility of SETTLE in the case of a bulky mass in patients over 70 years old, particularly in the lower neck. Herein, we report a case of the oldest patient so far. The patient underwent a right lobectomy of the thyroid and mass excision. Follow-up CT scans after 6 months revealed no local recurrence. Surgery is the gold standard treatment for SETTLE. Chemotherapy and radiotherapy could be another possible option for patients with advanced stage SETTLE.

Low-Dose Radioactive Iodine Ablation Is Sufficient in Patients With Small Papillary Thyroid Cancer Having Minor Extrathyroidal Extension and Central Lymph Node Metastasis (T3 N1a).

PURPOSE: The aim of this study was to evaluate the effectiveness of low-dose radioactive iodine (RAI) ablation in patients with small papillary thyroid cancer (PTC) exhibiting microscopic extrathyroidal extension (mETE) and central lymph node (CLN) metastasis. METHODS: Among patients who underwent RAI ablation between March 2007 and February 2014, those who had small PTCs (≤2 cm), as well as mETE and CLN metastasis (T3 N1a M0), were enrolled. Response to ablation and long-term outcomes were assessed and compared according to the administered RAI dose. Factors associated with unsuccessful ablation were also determined. RESULTS: A total of 180 patients were included in the study. Eighty-eight patients had been treated with 1110 MBq (low-dose group) and 92 with 2960 MBq (high-dose group) of RAI. There were no significant differences in the responses to ablation (P = 0.810) and long-term outcomes (P = 0.663) between both groups. Among all patients enrolled, 13 did not achieve successful ablation at long-term follow-up. Logistic regression found that a high ratio of metastatic nodes was a significant factor for predicting unsuccessful ablation. CONCLUSIONS: Low-dose RAI ablation did not produce significantly different responses or long-term outcomes in patients with small PTCs exhibiting mETE and CLN metastasis. These findings suggest that low-dose ablation may be sufficient in this specific group of intermediate-risk patients, although careful selection is required for patients with a high ratio of metastatic nodes.

Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis.

Bcl2 family proteins play an important role in the resistance of thyroid cancer cells to apoptosis induced by chemotherapeutic drugs and targeted therapies. BH3-profiling of seven fresh primary papillary thyroid cancer (PTC) tumors showed dependence for survival on Bcl-xL (2/7), Bcl2 (2/7), and Mcl-1 (2/7), while the majority of thyroid cell lines were mainly dependent on Bcl-xL. Targeting Bcl2 family proteins with the BH3 mimetic, ABT-737, while simultaneously inhibiting ERK pathway proteins with PLX4720 and PD325901 was shown to induce significantly high apoptosis in the majority of cell lines (8505c, SW1736, HTh7, BCPAP) and moderate apoptosis in the TPC-1 cell line. In orthotopic thyroid cancer mouse models of 8505c and BCPAP, treatment with the triple drug combination reduced the size of the tumors and showed significantly higher numbers of cells undergoing apoptosis. This treatment increased the expression of pro-apoptotic protein Bim, while decreasing anti-apoptotic protein Mcl-1. Our results suggest that analyzing the results of BH3-profiling along with the mutational status of tumor can reveal an effective therapy for targeted, personalized treatment of aggressive thyroid cancer.

Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer.

The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53-/- murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3±174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm3, P=0.023) or PD-L1 antibody (716.7±62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC.

Osteopontin levels in patients with papillary thyroid cancer according to the presence of Hashimoto's thyroiditis.

BACKGROUND: Human papillary thyroid carcinoma (PTC) is often associated with Hashimoto's thyroiditis (HT); their coexistence improves PTC prognosis. Osteopontin, a secreted glycoprotein, plays a role in cell survival, immunity, and tumor progression, its expression being associated with a poor prognosis and metastasis in several malignancies. Osteopontin overexpression correlates with aggressive clinicopathological features in PTC. Lymph node metastases and large tumor size positively correlate with osteopontin positivity. This study aimed to: (1) confirm osteopontin overexpression in human PTC samples; (2) compare osteopontin expression levels in PTC cases with and without HT; and (3) identify correlations between tumor aggressiveness and osteopontin expression levels. MATERIALS AND METHODS: Plasma osteopontin was assessed in 45 patients with PTC, 22 patients with PTC and HT, and 24 healthy controls by enzyme-linked immunosorbent assay. Thyroid tissue osteopontin mRNA and protein levels were analyzed by reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: Plasma osteopontin levels were significantly higher in PTC patients than in healthy controls. Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone. In advanced disease stage cases, osteopontin mRNA and protein expression levels were lower in patients with PTC and HT than in those with PTC alone. However, the osteopontin expression level was not significantly associated with the TNM stage. CONCLUSIONS: Plasma osteopontin, tissue osteopontin mRNA, and tissue osteopontin protein levels were significantly lower in patients with PTC and HT than in those with PTC alone, suggesting that HT attenuates PTC aggressiveness through negative regulation of osteopontin expression.

Curcumin Enhances Docetaxel-Induced Apoptosis of 8505C Anaplastic Thyroid Carcinoma Cells.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans, and its progression is poorly controlled by existing therapeutic methods. Curcumin has been shown to suppress inflammation and angiogenesis. In this study, we evaluated whether curcumin could augment docetaxel-induced apoptosis of ATC cells. We also analyzed changes in nuclear factor κB (NF-κB) and cyclooxygenase-2 (COX-2) expression levels to delineate possible mechanisms of their combined action. METHODS: ATC cells were cultured and treated with curcumin and docetaxel alone or in combination. The effects on cell viability were determined by MTS assay. Apoptosis was assessed by annexin V staining and confirmed by flow cytometric analysis. Caspase, COX-2, NF-κB levels were assayed by Western blotting. RESULTS: Curcumin combined with docetaxel led to lower cell viability than treatment with docetaxel or curcumin alone. Annexin V staining followed by flow cytometric analysis demonstrated that curcumin treatment enhanced the docetaxel-induced apoptosis of ATC cells. Additionally, curcumin inhibited docetaxel-induced p65 activation and COX-2 expression. CONCLUSION: We conclude that curcumin may enhance docetaxel's antitumor activity in ATC cells by interfering with NF-κB and COX-2. Our results suggest that curcumin may emerge as an attractive therapeutic candidate to enhance the antitumor activity of taxanes in ATC treatment.

Papillary thyroid carcinoma with thyroiditis: lymph node metastasis, complications.

PURPOSE: The aim of this study was to evaluate the clinicopathologic characteristics of papillary thyroid cancer with thyroiditis, and to determine the rate of its complications for it. METHODS: A retrospective review of 1,247 patients with papillary thyroid cancer who underwent primary thyroidectomy was performed. Among them, 316 patients had thyroiditis (group I) while 931 patients had no thyroiditis (group II), as reflected in the final pathologic reports. The two groups' clinicopathologic results and rate of complications were compared. RESULTS: Female gender, preoperative hypothyroidism, total thyroidectomy, no extrathyroid extension, no lymphovascular invasion, and no perineural invasion were associated with group I. More central lymph nodes were removed in group I than in group II, but there were fewer central lymph nodes with metastasis in group I than in group II. For the lateral lymph nodes, the two groups had the same numbers of removed nodes and nodes with metastatic tumor. Multivariate analysis revealed female predominance, more cases of preoperative hypothyroidism, more dissected lymph nodes, and fewer lymph nodes with metastasis in group I. Among the patients who underwent lobectomy, postoperative hypothyroidism occurred more in group I than in group II (P < 0.001). There was no difference in postoperative complications between the two groups. CONCLUSION: Papillary thyroid cancer with thyroiditis showed less aggressive features. Postoperative hypothyroidism occurred more in the patients with thyroiditis.

Impact of preserving the parathyroid glands on hypocalcemia after total thyroidectomy with neck dissection.

PURPOSE: The aims of this study were to determine the incidence and evaluate the risk factors for hypocalcemia after total thyroidectomy and to investigate how many parathyroid glands should be preserved to prevent postoperative hypocalcemia. METHODS: From March 2007 to February 2011, a retrospective review of 866 patients who underwent total thyroidectomy and node dissection for thyroid cancer was performed. The incidence and predisposing factors for hypocalcemia were analyzed. Among them, a total of 191 cases had four of their parathyroid glands identified intraoperatively. These patients were then divided into one preserved parathyroid gland group (group I, n = 22) and two or more preserved parathyroid glands group (group II, n = 169). The incidence of hypocalcemia with regards to the number of preserved parathyroid glands was determined and the results between the two groups were compared. The total calcium, ionized calcium and parathyroid hormone levels were compared between the two groups. RESULTS: The overall incidence of transient and permanent hypocalcemia was 9.2% and 0.5%, respectively. The decreased number of preserved parathyroid gland and increased number of removed central lymph node were the significant risk factors for developing postoperative hypocalcemia. In 191 cases identified with four parathyroid glands, the incidence of hypocalcemia was related to the number of preserved glands (group I, 22.7%; group II, 3.0%; P < 0.001). CONCLUSION: The insufficient number of preserved parathyroid glands is the only cause of hypocalcemia after total thyroidectomy and node dissection. At least one preserved parathyroid gland may prevent postoperative permanent hypocalcemia.

Parathyroid carcinoma with lung metastasis in a thirteen-year-old girl.

Parathyroid carcinoma is a rare disease in pediatric patients. We present a case of a 13-year-old girl who presented to the Thyroid Department for an asymptomatic palpable neck mass for 1 year. The high levels of calcium, ionized calcium, and parathyroid hormone level along with parathyroid scintigraphy studies suggested primary hyperparathyroidism. Parathyroid carcinoma was confirmed by biopsy and pathologic examination after resection. Six months postoperatively, persistent hypercalcemia and multiple lung metastases were found on computed tomography. Bilateral lung wedge resection was performed. En bloc resection for primary parathyroid carcinoma and aggressive resection of metastatic disease is the most effective treatment to control hypercalcemia.

Patterns and predictive factors of lateral lymph node metastasis in papillary thyroid microcarcinoma.

OBJECTIVE: To determine the incidence and patterns of and to evaluate the predictive factors for lateral cervical lymph node metastasis (LNM) in papillary thyroid microcarcinoma (PTMC). STUDY DESIGN: Case series with chart review. SETTING: Academic university hospital. SUBJECTS AND METHODS: From March 2007 to September 2010, a retrospective review was performed of 490 patients with PTMC who underwent total thyroidectomy and central lymph node dissection with or without lateral cervical lymph node dissection. The clinicopathologic results were reviewed, and the incidence and patterns of lateral cervical lymph node metastasis were analyzed. RESULTS: The overall frequency of central and lateral LNM was 39.6% and 3.0%, respectively. The incidence of lateral lymph node metastasis in level IIa, III, IV, Vb, IIb, and Va was 46.7%, 53.3%, 73.3%, 6.7%, 6.7%, and 20.0%, respectively. Lateral LNM without central LNM was observed in 3 (0.6%) cases of PTMC. A multivariate analysis revealed that the predictive factors for the presence of lateral lymph node metastasis are male sex, increased tumor size, T4 stage, and pathologic central lymph node metastasis. CONCLUSION: Although lateral LNM was rare, the surgeon should perform thorough preoperative studies to look for lateral LNM in cases of PTMC if the patient is male, has a relatively larger tumor size, and has aggressive mass and also to look for the possibility of skip metastasis. Lymph node metastasis involving the spinal accessory chain (IIb) was not that rare, and careful level IIb lymph node dissection should be considered for patients who will undergo a modified radical neck dissection for lateral LNM.

Expression of AITR and AITR ligand in breast cancer patients.

Human activation-inducible TNF receptor (AITR) is a new member of the tumor necrosis factor family and expressed on peripheral blood mononuclear cells (PBMC) and leukocytes. Its ligand (AITRL) is expressed in endothelial cells. This study aimed to evaluate the presence and role of AITR and AITRL in patients with breast cancer. Expression of AITR and AITRL on PBMC and breast cancer cells was determined by flow cytometry, RT-PCR and fluorescence microscopy. Soluble (s) AITR and sAITRL were detected in serum of breast cancer patients by ELISA. AITR and AITRL were constitutively expressed in T cells, B cells, monocytes and monocyte-derived dendritic cells of breast cancer patients. AITRL was overexpressed in breast cancer cells. The levels of sAITRL were significantly increased in serum of breast cancer patients compared with the healthy control. This study suggests that AITR and AITRL may play an important role in tumor growth and survival in breast cancer.