Role of Prophylactic Central Compartment Lymph Node Dissection on the Outcome Of Patients With Papillary Thyroid Carcinoma and Synchronous Ipsilateral Cervical Lymph Node Metastases.

OBJECTIVE: Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported. METHODS: We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed. RESULTS: The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%). CONCLUSION: In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number of 131I treatments. However, pCCND is severely affected by a higher percentage of permanent hypoparathyroidism, even in the hands of expert surgeons. ABBREVIATIONS: IQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound.

Metastasis of renal cell carcinoma to the parathyroid gland 16 years after radical nephrectomy: A case report.

Renal cell carcinoma (RCC) has a high metastatic potential, and most commonly metastasizes via the bloodstream, although lymphatic metastases also occur. RCC is well-known for its propensity to metastasize to unusual sites, and late metastasis, even after a number of years, is common. The occurrence of RCC metastasis to the head and neck region is uncommon, and occurs primarily in the thyroid gland and in patients with widespread dissemination. Involvement of the parathyroid gland in metastatic carcinoma is extremely rare. In the present report, a case of metastasis confined to the parathyroid gland is described, likely with intrathyroidal localization, arising from a RCC that occurred 16 years after nephrectomy. A 66-year-old man was referred to the Department of Surgery of the University Hospital of Pisa (Pisa, Italy) with a preoperative fine-needle aspiration diagnosis of a follicular lesion in the context of nodular goiter of the thyroid gland. The previous medical history of the patient included a right nephrectomy for the treatment of clear cell RCC in February 1997. No other distant metastases were identified as of the latest follow-up in March 2014. At the time of thyroid surgery, the thyroid and parathyroid function tests were normal. The gross appearance of the surgical specimen was a multinodular goiter with a solid nodule measuring 33 mm on the left lobe of the thyroid gland. Microscopic examination revealed a completely encapsulated lesion consisting of clear cells arranged in a solid pattern and intermixed with fragments of parathyroid tissue. Following immunohistochemical examination, the clear cell lesion was negative for thyroid transcription factor-1 and thyroglobulin and strongly positive for epithelial membrane antigen, cluster of differentiation 10 and vimentin. To the best of our knowledge, this is the second case of metastasis to the parathyroid gland from a RCC reported in the literature.

Minimally invasive video-assisted thyroidectomy (MIVAT) from A to Z.

A minimal access procedure does not necessarily mean that it is minimally invasive. However, as its name implies, MIVAT is a truly minimally invasive treatment modality. The advantages it offers over its conventional counterpart are indeed related to its minimally invasive nature. Furthermore, this nature has not compromised its ability to accomplish its purpose both safely and effectively. Ever since its introduction in the late 1990s, MIVAT has been progressively evolving. The indications for this procedure, which was initially surrounded by skepticism, have been expanding. Benign thyroid pathology is now considered only one of its indications among others. This article provides a detailed description of this minimally invasive, maximally effective and patient satisfying procedure so that it may be adopted by more surgeons around the globe for better patient care and to also encourage the development of further future advancements.

Increased risk of papillary thyroid cancer in systemic sclerosis associated with autoimmune thyroiditis.

OBJECTIVES: Patients with SSc have an increased risk of malignancy compared with the general population. Before now, no study has evaluated the risk of thyroid cancer (TC) in SSc patients. The aim of the study was to evaluate the prevalence of TC in SSc patients. METHODS: We studied the prevalence of TC in 327 unselected SSc patients in comparison with two population-based, gender- and age-matched control groups (654 subjects from an iodine-deficient area and 654 subjects from an iodine-sufficient area). Thyroid status was assessed by measurement of circulating thyroid hormones and autoantibodies, thyroid ultrasonography and fine-needle aspiration cytology (when necessary). RESULTS: Circulating thyroid-stimulating hormone, anti-thyroglobulin and anti-thyroperoxidase antibody levels, and the prevalence of hypothyroidism were significantly higher in SSc patients (P < 0.01, for all). Six patients with papillary TC (PTC) were detected among SSc patients, whereas only one case was observed in each of controls 1 and 2 (P = 0.007, for both). In SSc all patients with TC had evidence of thyroid autoimmunity vs 40% of the other SSc patients (P = 0.001). CONCLUSION: These data suggest a high prevalence of papillary TC in SSc patients, in particular in the presence of thyroid autoimmunity; careful thyroid monitoring would be opportune during the follow-up of these patients.

New therapies for dedifferentiated papillary thyroid cancer.

The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, which fails to respond to RAI, exhibiting a more aggressive behavior. The lack of specific, effective and well-tolerated drugs, the scarcity of data about the association of multi-targeting drugs, and the limited role of radioiodine for dedifferentiated thyroid cancer, call for further efforts in the field of new drugs development. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, BRAF (B-RAF proto-oncogene, serine/threonine kinase) gene mutations, RAS (rat sarcoma) mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways playing a crucial role in the development of thyroid cancer. Targeted novel compounds have been demonstrated to induce clinical responses and stabilization of disease. Sorafenib has been approved for differentiated thyroid cancer refractory to RAI.

Antineoplastic activity of the multitarget tyrosine kinase inhibitors CLM3 and CLM94 in medullary thyroid cancer in vitro.

BACKGROUND: We report the antineoplastic and anti-angiogenic activity of the pyrazolo[3,4-d]pyrimidine derivative CLM3 and the cyclic amide CLM94, both multiple tyrosine kinase inhibitors (TKIs), in human primary medullary thyroid cancer (P-MTC) cells, and in vitro in the medullary thyroid cancer (MTC) cell lines TT (harboring a RET C634W activating mutation) and MZ-CRC-1 (carrying the MEN2B RET mutation Met891Thr). METHODS: The antiproliferative and proapoptotic effects of CLM3 and CLM94 (1, 5, 10, 30, and 50 µmol/L) were tested in P-MTC cells obtained at operation, and in TT cells. In addition, the antiproliferative effects of CLM3 and CLM94 (0.005, 0.05, 0.5, and 5 µmol/L) were tested in TT and MZ-CRC-1 cells after 7 days of treatment to compare the results with those previously reported in the literature. RESULTS: CLM3 and CLM94 (30 or 50 µmol/L) inhibited (P < .01) the proliferation of the P-MTC cells, TT cells, and MZ-CRC-1 cells and increased the level of apoptosis in a dose-dependent manner at 10, 30, and 50 µmol/L (P < .001), while having no effect on migration or invasion. The inhibition of proliferation by CLM3 and CLM94 was similar among P-MTC cells with/without RET mutations, and similar effects were observed regarding the increased level of apoptosis. Furthermore, CLM3 and CLM94 significantly decreased vascular endothelial growth factor-A expression in TT cells. CONCLUSION: The antitumor activities of the multiple TKIs CLM3 and CLM94 were demonstrated in both primary MTC cultures as well as 2 established MTC cell lines in vitro, opening an avenue for future clinical evaluations.

CLM29, a multi-target pyrazolopyrimidine derivative, has anti-neoplastic activity in medullary thyroid cancer in vitro and in vivo.

CLM29 (a pyrazolo[3,4-d]pyrimidine, that inhibits RET, epidermal growth factor receptor, vascular endothelial growth factor receptor, and has an anti-angiogenic activity) has anti-neoplastic activity in papillary dedifferentiated thyroid cancer. Here we tested CLM29 in medullary thyroid cancer (MTC), in primary MTC cells (P-MTC) obtained at surgery, and in TT cells harboring (C634W) RET mutation. CLM29 (10, 30, 50 µM) inhibited significantly (P<0.001) the proliferation, and increased the percentage of apoptotic P-MTC, TT and human dermal microvascular endothelial cells. The inhibition of proliferation by CLM29 was similar in P-MTC cells with/without RET mutation. TT cells were injected sc in CD nu/nu mice, and tumor masses became detectable between 20 and 30 days after xenotransplantation; CLM29 (50mg/kg/die) reduced significantly tumor growth and weight, and microvessel density. The anti-tumor activity of CLM29 has been shown in MTC in vitro, and in vivo, opening the way to a future clinical evaluation.

Variable modulation by cytokines and thiazolidinediones of the prototype Th1 chemokine CXCL10 in anaplastic thyroid cancer.

Until now, no data are present in literature about the prototype Th1 chemokine (C-X-C motif) ligand 10 (CXCL10) in anaplastic thyroid cancer (ATC). This study aimed to test in "primary human ATC cells" (ANA) vs "normal thyroid follicular cells" (TFC): (a) CXCL10 secretion basally and after interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α stimulation; (b) peroxisome proliferator-activated receptor (PPAR)-γ activation by thiazolidinediones, rosiglitazone or pioglitazone, on CXCL10 secretion, on proliferation and apoptosis in ANA. We demonstrate that: (a) ANA, but not TFC, produced basally CXCL10, and did so in half of cases; (b) IFN-γ stimulated dose-dependently CXCL10, in ANA and TFC; (c) TNF-α did not induce CXCL10 secretion, in ANA and TFC; (d) IFN-γ+TNF-α induced a synergistic but variable release of CXCL10 in the different ANA preparations, while it was more reproducible in TFC; (e) rosiglitazone action on CXCL10 in ANA was inhibitory in 2/6, stimulatory in 1/6 and nil in 3/6, whereas it was inhibitory in TFC; (f) rosiglitazone inhibition of proliferation in ANA was not associated with the effect on CXCL10; (g) nuclear factor-κB and ERK1/2 were basally activated in ANA, increased by IFN-γ+TNF-α, and rosiglitazone inhibited that activation. On the whole, the present data first show that ANA cells are able to produce CXCL10, basally and under the influence of cytokines. However, the pattern of modulation by IFN-γ, TNF-α or thiazolidinediones is extremely variable, suggesting that the intracellular pathways involved in the chemokine modulation in ATC have different types of deregulation.

New targeted therapies for thyroid cancer.

The increasing incidence of thyroid cancer is associated with a higher number of advanced disease characterized by the loss of cancer differentiation and metastatic spread. The knowledge of the molecular pathways involved in the pathogenesis of thyroid cancer has made possible the development of new therapeutic drugs able to blockade the oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases [vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptors (PDGFR)] involved in cellular growth and proliferation. Some clinical trials have been conducted showing the ability of targeted therapies (sorafenib, sunitinib, axitinib, imanitib, vandetanib, pazopanib, gefitinib) in stabilizing the course of the disease. Until now, however, no consensus guidelines have been established for patient selection and more data on toxicities and side effects are needed to be collected.

Incidental thyroid carcinoma in a large series of consecutive patients operated on for benign thyroid disease.

BACKGROUND: The diagnosis of incidental thyroid carcinoma (ITC) in patients operated on for a benign disease is frequent. This study aims to determine both its clinical effect and the possibility of identifying this class of patients preoperatively. METHODS: A total of 998 consecutive patients (697 women and 301 men; mean age, 49.5 years) undergoing surgery for benign thyroid pathology in a single institution were studied. The mean time between first diagnosis of thyroid disease and operation was 9.0 years (range, 0-50 years). All patients underwent at least one ultrasonography before surgery, and 678 patients underwent fine-needle aspiration cytology. Patients with undetermined cytology or follicular nodules were excluded from the study. RESULTS: Histology revealed an ITC in 104 patients (10.4%): 99 had a papillary carcinoma. Mean and median diameters of ITC were 1.4 and 0.7 cm, respectively (range, 0.1-7.5 cm). In 43 patients, the tumour size was greater than 1 cm, whereas it exceeded 2 cm in 25 patients. Tumours were multicentric in 19.8% of the patients and occurred in 8.2% of patients with nodular toxic goiter, 8.7% of patients with toxic diffuse goiter and 13.8% of patients with multinodular goiter. DISCUSSION: The results confirm the high frequency of ITC. ITC was more frequent in euthyroid patients than in thyrotoxic patients (P < 0.03). Sex, age, thyroid volume and interval between diagnosis and surgery did not significantly influence its incidence. The majority of ITC was represented by microcarcinomas, but in approximately 25% of patients, the tumour size was greater than 2 cm. The role played by FNAC in excluding malignancies proved to be fairly inconclusive.

Ultrasonography estimated thyroid volume: a prospective study about its reliability.

Ultrasonography is supposed to provide a reliable preoperative estimate of thyroid volume. This prospective study compares the estimated thyroid volume (EV) to real volume (MV), obtained by measuring the excised gland after surgery. One hundred one patients undergoing total thyroidectomy were selected for the study. Indications for surgery were: multinodular goiter, diffuse toxic goiter (DTG), uninodular disease. In all cases, ultrasound was repeated 1 month after surgery to verify complete thyroid removal. EV was underestimated in 89 cases; it perfectly matched the MV in 5 and was overestimated in 7. Mean EV was 28.3 mL (range, 7-50) and mean MV 36.2 mL (range, 7-76); this difference was statistically significant (p < 0.0001). Patients were then divided in groups according to EV (< or > than 25 mL) and thyroid morphology. Highly significant differences were found between all groups (p < 0.0001) except the DTG population, where the difference was less significant (p < 0.042). The study demonstrates that a correct preoperative measurement of the thyroid gland is not achievable because the volume estimated by ultrasound is largely underestimated in comparison to the real volume of the excised gland. Nevertheless ultrasound is more reliable in DTG than in other thyroid diseases. Increasing the number of cases may help to verify a new mathematical model.

Extent of surgery in thyroglossal duct carcinoma: reflections on a series of eighteen cases.

The occurrence of carcinoma of the thyroglossal duct remnant (TDRCa) is reported to be less than 1%. We retrospectively analyzed 18 cases (14 females, 4 males; mean age, 38.17 years) of TDRCa who underwent surgery in our department, to evaluate the correct workup for diagnosis and treatment. Nine patients underwent a total thyroidectomy and a Sistrunk procedure (SP) whereas 8 underwent a completion total thyroidectomy after a postoperative diagnosis of TDRCa. One patient was diagnosed with TDRCa several years after total thyroidectomy for goiter. Postoperatively all patients were given radioiodide and levothyroxine therapy. Mean follow-up was 85 months. No patient died of tumor-related disease. Thyroglossal duct neoplasms were represented by papillary carcinoma in 16 cases; thyroid histology demonstrated papillary carcinoma in 6 cases (33.3%). Three patients demonstrated single regional node metastasis and only one of them demonstrated the presence of malignant thyroid disease. When clinical diagnosis of thyroglossal duct cyst is made, the workup should be completed by ultrasound (US) scan and fine-needle aspiration cytology (FNAC) in order to plan the correct surgery for a possible TDRCa. Total thyroidectomy should always be considered with SP to permit the correct treatment and follow-up in those patients. Long-term survival of patients with cTDRCa is excellent.

Minimally invasive video-assisted thyroidectomy for papillary carcinoma: a prospective study of its completeness.

BACKGROUND: The effectiveness of minimally invasive video-assisted thyroidectomy (MIVAT) in papillary thyroid carcinoma is still debated. Some are concerned about this procedure in patients with thyroid cancer. This prospective study aimed to demonstrate that near-total thyroidectomy can be performed by MIVAT with similar results compared with open thyroidectomy. METHODS: A total of 33 patients with a thyroid nodule proven to be a papillary thyroid carcinoma underwent a near-total thyroidectomy. They were randomly assigned to group A (n = 16) or group B (n = 17) who were treated either by MIVAT or conventional near-total thyroidectomy, respectively. Iodine-131 thyroid bed uptake and serum thyroglobulin were measured 1 month after operation. Data were analyzed by unpaired t test and Mann-Whitney statistic methods. RESULTS: . Mean iodine-131 uptake was 5.1 +/- 4.9% in group A and 4.6 +/- 6.7% in group B. Mean thyroglobulin serum levels were 5.3 +/- 5.8 ng/mL in group A and 7.6 +/- 21.7 ng/mL in group B. The differences were not statistically significant. CONCLUSIONS: The results of this study showed that the completeness obtained with MIVAT is similar to that obtained with open thyroidectomy, with the great advantage of a minimal neck wound. No conclusions can be drawn in terms of influence of MIVAT on the outcome of the patients with small papillary thyroid carcinoma.