Sentinel lymph node mapping: current applications and future perspectives in thyroid carcinoma.

Sentinel lymph node (SLN) mapping is a standard, minimally-invasive diagnostic method in the surgical treatment of many solid tumors, as for example melanoma and breast cancer, for detecting the presence of regional nodal metastases. A negative SLN accurately indicates the absence of metastases in the other regional lymph nodes (LN), thus avoiding unnecessary lymph nodal dissection. Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma (TC) with cervical LN metastases at diagnosis in 20-90%, and nodal involvement correlates with local persistence/recurrence. The SLN in PTC is an intraoperative method for staging preoperative N0 patients and for detecting metastatic LNs "in and outside" the cervical LN central compartment; it represents an alternative method to prophylactic central neck node dissection. In this review we summarize different methods and results of the use of SLN in TC. The SLN identification techniques currently used include the selective vital-dye (VD) method, 99mTc-nanocolloid planar lymphoscintigraphy with intraoperative use of a hand-held gamma probe (LS), the combination LS + VD, and the combination LS and preoperative SPECT-CT (LS + SPECT/CT). The application of the SLN procedure in TC has been described in many studies, however, the techniques are heterogeneous, and the role of SLN in TC, with indications, results, advantages and limits, is still debated.

Overexpression of miR-375 and L-type Amino Acid Transporter 1 in Pheochromocytoma and Their Molecular and Functional Implications.

Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between 18F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing 18F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between 18F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of 18F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo.

Predictivity of clinical, laboratory and imaging findings in diagnostic definition of palpable thyroid nodules. A multicenter prospective study.

PURPOSE: To assess the role of clinical, biochemical, and morphological parameters, as added to cytology, for improving pre-surgical diagnosis of palpable thyroid nodules. METHODS: Patients with a palpable thyroid nodule were eligible if surgical intervention was indicated after a positive or suspicious for malignancy FNAC (TIR 4-5 according to the 2007 Italian SIAPEC-IAP classification), or two inconclusive FNAC at a ≥3 months interval, or a negative FNAC associated with one or more risk factor. Reference standard was histological malignancy diagnosis. Likelihood ratios of malignancy, sensitivity, specificity, negative (NPV), and positive predictive value (PPV) were described. Multiple correspondence analysis (MCA) and logistic regression were applied. RESULTS: Cancer was found in 433/902 (48%) patients. Considering TIR4-5 only as positive cytology, specificity, and PPV were high (94 and 91%) but sensitivity and NPV were low (61 and 72%); conversely, including TIR3 among positive, sensitivity and NPV were higher (88 and 82%) while specificity and PPV decreased (52 and 63%). Ultrasonographic size ≥3 cm was independently associated with benignity among TIR2 cases (OR of malignancy 0.37, 95% CI 0.18-0.78). In TIR3 cases the hard consistency of small nodules was associated with malignity (OR: 3.51, 95% CI 1.84-6.70, p < 0.001), while size alone, irrespective of consistency, was not diagnostically informative. No other significant association was found in TIR2 and TIR3. CONCLUSIONS: The combination of cytology with clinical and ultrasonographic parameters may improve diagnostic definition of palpable thyroid nodules. However, the need for innovative diagnostic tools is still high.

Specifying the molecular pattern of sporadic parathyroid tumorigenesis-The Y282D variant of the GCM2 gene.

OBJECTIVE: Sporadic carcinoma of the parathyroid glands is a rare malignant neoplasia. The GCM2 gene encodes a transcription factor that is crucial to embryonic parathyroid development. The Y282D variant of GCM2 exhibits increased transcriptional activity, and the presence of this variant is significantly associated with a higher prevalence of primitive hyperparathyroidism. The present study investigated the prevalence of the Y282D variant of the GCM2 gene and its association with clinical parameters in patients with a definitive histological diagnosis of sporadic parathyroid carcinoma (SPC) or atypical adenoma (AA).

Aberrant right subclavian artery ("arteria lusoria") without the known associated nerve anomaly: an "anomaly of the anomaly"? A clinical case and review of the literature.

The "non-recurrent" course of the inferior laryngeal nerve (ILN) is an anatomical variant which must be borne in mind during thyroid surgery. The "non-recurrent" course of the ILN on the right side is associated with the aberrant right subclavian artery (arteria lusoria), and, on the left, is described in situs viscerum inversus. We present a case in which the "arteria lusoria" was not associated with the non-recurrent right ILN. The aims of this paper are to report this "anomaly of the anomaly" to surgeons who may be unaware of it on the one hand and on the other to emphasize that this is the only case so far reported in the literature. Moreover we proposed to explain embryologically these unexpected findings.

Estrogen and thyroid cancer is a stem affair: A preliminary study.

Gender influences Papillary Thyroid Cancer (PTC) with an incidence of 3:1 when comparing women to men with different aggressiveness. This gender discrepancy suggests some role of sex hormones in favoring the malignant progression of thyroid tissue to cancer. Estrogens are known to promote Stem Cell self-renewal and, therefore, may be involved in tumor initiation. The goals of these studies are to investigate the underlying causes of gender differences in PTC by studying the specific role of estrogens on tumor cells and their involvement within the Cancer Stem Cell (CSC) compartment. Exposure to 1nmoll-1 Estradiol for 24h promotes growth and maintenance of PTC Stem Cells, while inducing dose-dependent cellular proliferation and differentiation following Estradiol administration. Whereas mimicking a condition of hormonal imbalance led to an opposite phenotype compared to a continuous treatment. In vivo we find that Estradiol promotes motility and tumorigenicity of CSCs. Estradiol-treated mice inoculated with Thyroid Cancer Stem Cell-enriched cells developed larger tumor masses than control mice. Furthermore, Estradiol-pretreated Cancer Stem cells migrated to distant organs, while untreated cells remained circumscribed. We also find that the biological response elicited by estrogens on Papillary Thyroid Cancer in women differed from men in pathways mediated. This could explain the gender imbalance in tumor incidence and development and could be useful to develop gender specific treatment of (PTC).

Lymphoscintigraphy in Differentiated Thyroid Cancer.

There is considerable variability in the surgical approach to differentiated thyroid cancer regarding the decision to explore and remove central or central and lateral compartment lymph nodes. Much as sentinel lymph node sampling has improved the decision to remove axillary nodes for breast cancer, vital dye and lymphoscintigraphy with lymph node sampling may direct the surgical approach to differentiated thyroid cancer.

Incidental medullary thyroid microcarcinoma revealed by mild increase of preoperative serum calcitonin levels: therapeutic implications.

To investigate whether further, diagnostic procedures should be recommended in patients with slight increase of preoperative serum basal calcitonin (bCT) levels in whom surgical treatment can be recommendable. Fourteen consecutive patients with nodular thyroid disease underwent thyroidectomy in our center for suspected medullary thyroid microcarcinoma (MTC) because their serum bCT levels were slightly higher than the upper limit of normal range. Serum bCT was measured by radioimmunoassay, normality range = 0-20 ng/L. Surgical specimens were examined by the same pathologist using histologic and immunohistochemistry techniques. An extensive search for parafollicular C-cell hyperplasia (CCH) and/or microscopic MTC foci was performed. At preoperative ultrasound, a single thyroid nodule was depicted in three patients while a multinodular goiter in 11. The bCT values ranged between 24.4 and 94.6 ng/L, median 42.2 ng/L while the pentagastrin-stimulated CT (sCT) values by pentagastrin test ranged between 61.5 and 1,262 ng/L, median 245.0 ng/L. Total thyroidectomy was performed in 13 patients, and lobectomy in the other one; central node dissection was also performed in eight cases. At histology, MTC was diagnosed in nine patients (64.3 %), showing a median maximum diameter of 6.1 mm (range, 1.5-17 mm); CCH was diagnosed in the other five patients (35.7 %). The pentagastrin stimulation test was obtained in all patients. It is worth noting that a very high increase of sCT >100 ng/mL was observed in 5/9 patients with MTC and in 2/4 patients with HCC, therefore suggesting the absence of a relationship between the entity of response to pentagastrin test with a specific pathology (MTC vs. HCC). In six patients, the MTC was the nodule on which preoperative FNAC had been performed, while in other three patients preoperative FNAC had been performed on a different nodule from the MTC. Based on our experience, in case of the pentagastrin stimulation test with sCT <100 ng/L and a single nodule, the CT assay on FNAC may be useful, subsequently lobectomy with definitive histological diagnosis is recommended. In case of the Pg test with sCT <100 ng/L and bilateral goiter, total thyroidectomy with histological diagnosis is recommended. In this way, as for the surgical procedure, total thyroidectomy is recommended in cases of bilateral goiter, while lobectomy can be offered for cases with single nodes with serum dosage of bCT in the strict follow up. In case of the pentagastrin stimulating test with sCT <100 ng/L and bilateral goiter, total thyroidectomy with histological diagnosis is recommended.

A very rare bilateral adrenal tumor.

We report a case of very rare adrenal tumor. A 54-year-old patient was classified as affected by bilateral adrenal incidentaloma that surprisingly, on histology resulted solitary fibrous tumors. Solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm. Only five cases of localization of SFT in adrenal gland are reported in the literature, while the frequency of retroperitoneum localization is more frequent, about 30 cases. Immunohistochemically, SFT can be positive for CD34 antigen, vimentin, CD99, and bcl-2 and usually negative for cytokeratins, chromogranin A, NSE, neurofilaments, synoptophysin, and S-100. Surgical excision remains the main treatment in fact the recurrence is locoregional and correlated with positive margins due to incomplete excision, while distant metastases are correlated with atypical or malignant features.

FDG-PET/CT and parathyroid carcinoma: Review of literature and illustrative case series.

Parathyroid cancer is an uncommon malignant cancer and is associated with a poor prognosis. The staging of parathyroid cancer represents an important issue both at initial diagnosis and after surgery and medical treatment. The role of positron emission tomography/computed tomography (PET/CT) with 18F-Fluorodeoxyglucose (18F-FDG) as an imaging tool in parathyroid cancer is not clearly reported in the literature, although its impact in other cancers is well-defined. The aim of the following illustrative clinical cases is to highlight the impact of PET/CT in the management of different phases of parathyroid cancer. We describe five patients with parathyroid malignant lesions, who underwent FDG PET/CT at initial staging, restaging and post-surgery evaluation. In each patient we report the value of PET/CT comparing its findings with other common imaging modalities (e.g., CT, planar scintigraphy with 99mTc-sestamibi, magnetic resonance imaging) thus determining the complementary benefit of FDG PET/CT in parathyroid carcinoma. We hope to provide an insight into the potential role of PET/CT in assessing the extent of disease and response to treatment which are the general principles used to correctly evaluate disease status.

Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification.

OBJECTIVE: Medullary thyroid carcinoma (MTC) derives from the parafollicular C cells, being sporadic in 75% of cases and familial in 25%, due to RET proto-oncogene germinal mutations. In sporadic forms, stage at diagnosis is the most important negative prognostic factor. The aim of this study was to evaluate the prognostic impact of molecular and immunohistochemical markers in sporadic MTC. DESIGN AND METHODS: We studied 60 patients with sporadic MTC. For each case, we sought RET somatic mutations in the primary cancer and in lymph node metastases. The primary cancer also underwent immunohistochemical examination for Ki-67. RESULTS: A somatic RET mutation was found in 38% of patients, being M918T in 52% of them. We observed a statistically significant association between RET mutations and male gender (P<0.01), tumor size (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P<0.05), increased risk of persistent disease (P=0.01), and low overall survival (P<0.01). High Ki-67 levels were similarly associated with extra-thyroid spread (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P=0.01), and low overall survival (P=0.01). Combining somatic RET analysis with Ki-67 assessment seems to be useful for increasing the specificity of Ki-67 assessment alone and identifying patients with a more aggressive cancer: in our series, only the patients who died during the follow-up had both a somatic RET mutation and a Ki-67 expression level >50 cells/mm(2). CONCLUSIONS: The combined evaluation of RET and Ki-67 could act as an adjuvant prognostic marker useful for ameliorating the initial risk stratification of patients with sporadic MTC.

BRAF analysis by fine needle aspiration biopsy of thyroid nodules improves preoperative identification of papillary thyroid carcinoma and represents a prognostic factor. A mono-institutional experience.

BACKGROUND: The current preoperative diagnosis of a thyroid mass relies on microscopic evaluation of thyroid cells obtained by fine needle aspiration biopsy (FNAB). More recently, FNAB has been combined with molecular analysis to increase the accuracy of the cytological evaluation. In this mono-institutional prospective study, we evaluated whether the routine introduction of BRAF testing in thyroid FNAB could help ameliorate the preoperative recognition of papillary thyroid carcinoma (PTC) in "suspended" or malignant cytological categories. Moreover, we investigated the prognostic role of the BRAFV600E mutation in PTC. METHODS: BRAFV600E analysis was performed in thyroid FNAB from 270 patients classified into one of five cytological categories THY1, THY2, THY3, THY4, THY5. All subsequently underwent thyroidectomy±node dissection, from October 2008 to September 2009 in our Department. For each cytological category, we considered the definitive histological diagnosis of PTC and the presence of the BRAFV600E mutation. In 141 patients with a final tissue diagnosis of PTC, we correlated the presence of BRAFV600E with gender, age, histotype, TNM, size of the lesion, extracapsular extension, node metastases and multifocality. RESULTS: The prevalence of the BRAFV600E mutation, among PTCs at final tissue diagnosis, was 69%. It improved the FNAB diagnostic accuracy from 88% to 91%. The BRAFV600E mutation was correlated with older age, classical variant of PTC, advanced stages in patients > 45 years. CONCLUSIONS: BRAFV600E testing could play a role in improving the diagnostic accuracy of FNAB for PTC, representing a useful adjuvant tool in presurgical characterization of thyroid nodes in particular cases. There is an association between the BRAFV600E mutation and some clinico-pathological characteristics of PTC.

Rapid intraoperative parathyroid hormone assay in fine needle aspiration for differential diagnosis in thyroid and parathyroid surgery.

BACKGROUND: The purpose of our study was to investigate the efficacy of rapid intraoperative parathyroid hormone (rIO-PTH) analysis performed using material collected by fine needle aspiration as a parameter to distinguish anatomical structures which the surgeon is not able to identify clearly as parathyroid or lymph node during thyroid/parathyroid surgery. Before surgery, all patients gave written, informed consent. METHODS: We measured the rIO-PTH on 50 anatomical structures, 32 presumed parathyroids and 18 presumed lymph nodes from 22 patients, who underwent thyroid/parathyroid surgery between May and September 2009. RESULTS: The rIO-PTH values obtained on parathyroids ranged from 85.4 pmol/L to more than 2106 pmol/L, with a rIO-PTH median of 263.25 pmol/L. Results obtained on lymph nodes ranged from <0.52 pmol/L up to 20.4 pmol/L, with a rIO-PTH median equal to 1.31 pmol/L. Results of the Mann-Whitney test showed a rIO-PTH median significantly different (p<0.0001) between samples obtained from parathyroid glands and lymph node tissue. CONCLUSIONS: We demonstrated that rapid intraoperative measurement of parathyroid hormone is a good parameter for the differential diagnosis of parathyroid vs. lymph node tissue. We suggest extending the use of this technique to the field of parathyroid preservation during thyroid/parathyroid surgery in those cases where the parathyroids prove difficult to recognize on the basis of topographic or morphologic criteria.

Can we avoid inadvertent parathyroidectomy during thyroid surgery?

OBJECTIVES: To identify risk factors of inadvertent parathyroidectomy (IP) during thyroid surgery with the aim of decreasing the incidence of this unpleasant complication and to evaluate the impact on temporary and permanent hypocalcaemia following bilateral thyroidectomy. PATIENTS AND METHODS: All consecutive thyroid surgical procedures performed at the Special Surgical Pathology Department of Padova General Hospital and Padova University during one year (January-December 2005) were retrospectively reviewed. Demographic data as well as data on diagnosis, operative reports, pathology findings, and postoperative serum calcium values were collected. A total of 882 patients (F=685 M=197) were included in the study. The patients were divided into 2 groups: those with IP and those without IP, and their data were compared to find factors affecting the occurrence of IP. The impact of IP on residual early and late postoperative parathyroid function was assessed. Hypercalcaemic (calcium level below 2.10 mMol/L) patients were followed from 1 week to 3 years. RESULTS: Seventy of 882 patients (7.9%) were found to have IP. In 11 cases (16% of IP cases and 1.2 % of entire series) the parathyroid glands were completely intrathyroidal. The results of bivariate analysis showed young age (p=0.037), malignant disease (p<0.0001), total thyroidectomy with lymph node dissection (p<0.0001), low weight of thyroid specimen (p<0.0001), and non-visualisation of any parathyroid gland at operation (p<0.0001) as predictive factors for IP. Multivariate analysis revealed significant correlation between IP and malignant disease (p=0.004), and between lymph node dissection and permanent postoperative hypocalcaemia (p=0.018). The incidence rate of transient and permanent hypocalcaemia was higher in IP than in those without. The mean diameter of excised parathyroid glands was 3.2 mm, suggesting more extended or difficult surgical procedures. CONCLUSION: IP is not uncommon during thyroidectomy and is associated with a higher, though not statistically significant, incidence of transient and permanent postoperative hypocalcaemia. Malignant disease, lymph node dissection, non-visualization of any parathyroid gland at operation and younger age seem to be risk factors and should be considered by the surgeon. Further efforts must be taken to reduce the incidence beginning by avoiding parathyroid fragmentation.

99Tc Nanocolloid sentinel node procedure in thyroid carcinoma.

PURPOSE: The purposes of this study were to investigate the efficacy of radiocolloid lymphoscintigraphy and of handheld gamma probe procedure for sentinel lymph node biopsy (SLNB) in papillary thyroid carcinoma (PTC) and to evaluate its results in clinical staging. MATERIALS AND METHODS: Sixty-five PTC consecutive patients entered the study. Patients underwent radiocolloid lymphoscintigraphy before surgery. Intraoperative sentinel lymph node (SLN) localization was performed using a handheld gamma probe. They were followed up at 2, 6 months, and yearly. RESULTS: SLN metastases were diagnosed in 52%. Fifty-one patients underwent ablative 131-I therapy. The mean Tireoglobulin level in N0 vs N1 cases was 2.2 ng/ml vs 4.73 (p = 0.03) and 0.68 vs 2.1 ng/ml (p = 0.005) before and after 131-I therapy, respectively. CONCLUSIONS: In patients classified N0 by SLNB, ablative 131-I therapy could be avoided.

[The surgical treatment of the nodular goiter]. / Il trattamento chirurgico del gozzo nodulare.

BACKGROUND: The simple nodular goiter, the etiology of which is multifactorial, encompasses the spectrum from the incidental asymptomatic small solitary nodule to the large intrathoracic goiter, causing pressure symptoms as well as cosmetic complaints. The mainstay in the diagnostic evaluation is related to functional and morphological characterization with serum TSH and (some kind of) imaging. Because malignancy is just as common in patients with a multinodular goiter as patients with a solitary nodule, the increasing use of fineneedle aspiration biopsy (cytology) is supported Its management is still the cause of considerable controversy. Prevalence of nodular goiter and results of surgical treatment in a large series of patients operated on at our center are reported. METHODS: From January to December 2004, 1009 out of 1580 patients admitted to our Center underwent surgical treatment for thyroid disease. RESULTS: Nodular goiter accounted for 80% of the whole series. More in detail, toxic multinodular goiter was found in 13.5% of the patients, euthyroid multinodular goiter in 46.6%, single hyperplastic nodule in 2.3%, follicular lesion in 14%, Plummer's adenoma in 4.4%, relapsing goiter in 2.6% and thyroid cyst in 0.12%. Thyroid lobectomy was carried out in 20.8% of patients, while the remaining 79.2% underwent to total thyroidectomy. A carcinoma was incidentally found in 7.6% of the multinodular goiters. CONCLUSIONS: Surgery should be advocated for the treatment of thyroid nodules whenever a patient presents with either pressure symptoms, hyperthyroidism or follicular cytology. Serum TSH measurement, ultrasounds and fine needle aspiration cytology are the main diagnostic tools. Bilateral surgical exploration of the gland should be always carried out to assess the extension of the disease. Total or near total thyroidectomy in order to minimize the risk of recurrent nerve palsy and hypoparathyroidism represents the treatment of choice for bilateral goiter. Thyroid lobectomy with frozen section should be limited to unilateral nodular goiter.

Thyroidectomy and parathyroid hormone: tracing hypocalcemia-prone patients.

BACKGROUND: The aim of this prospective study was to identify patients at high risk of developing hypocalcemia after thyroidectomy on the basis of the parathyroid hormone (PTH) level on the first postoperative day. METHODS: We included 160 patients undergoing total thyroidectomy in a period of 6 months by the same surgical team in this study. In all patients the PTH level was measured before surgery on the day of surgery (PTH1), and on the first postoperative day (PTH2), whereas serum calcium level was measured daily until discharge. Patients were classified as hypocalcemic if they had a serum calcium level less than the normal range on the first postoperative day, independently of symptoms of hypocalcemia. RESULTS: At an average follow-up period of 5.9 months (range, 4-9 mo), 66 patients were considered hypocalcemic, 57 patients (35.6%) had a transient hypocalcemia, and 9 patients (5.6%) required calcium-vitamin D supplementation for persistent hypocalcemia. The mean PTH1 value was 54.4 +/- 17.2 pg/mL (median, 53.85 pg/mL), the mean PTH2 value was 22.8 +/- 13.3 pg/mL (median, 21 pg/mL). The mean PTH decrease in value was 51.54% +/- 27.4% (median, 51.83%; range, 4%-94%) and 43.7% of patients presented a PTH decrease of more than 50%. The presence of a postoperative hypocalcemia was statistical correlated both with the PTH2 level and with the PTH drop percent value (P < .001 and P = .002, respectively). With the use of the receiver operating characteristic curve, the maximum sum of the sensitivity and specificity for the correlation of PTH2 levels and hypocalcemia occurred at a PTH2 level of 9.6 pg/mL. CONCLUSIONS: The PTH measurement on the first postoperative day may be considered a useful method to predict postthyroidectomy hypocalcemia, thus avoiding prolonged hospitalization. Moreover, PTH dosage at first postoperative day is more reliable and less expensive than intraoperative quick PTH assay.

Characterization of a novel complex BRAF mutation in a follicular variant papillary thyroid carcinoma.

INTRODUCTION: Activating mutations of the BRAF oncogene are frequently detected in papillary thyroid carcinoma (PTC) and have been associated with a worse prognosis. The amino acid substitution V600E accounts for 90% of all oncogenic BRAF mutations and is typically detected in classic PTCs, whereas other less frequent BRAF mutations seem to be associated with other PTC histotypes. CASE: Screening for activating BRAF mutations in a series of 83 PTCs identified the most common V600E mutation in 39 cases (histologically, 38 classic PTCs and 1 sclerosing variant PTC) and a complex in-frame mutation involving amino acids V600-S605 in a stage III multicentric follicular variant PTC, occurring in a 50-year-old female patient, who was affected by hypothyroidism in autoimmune thyroiditis and had a family history of PTC and autoimmune thyroiditis. Since the identified BRAF mutation was novel in the literature, bioinformatic modeling was performed to predict its impact on BRAF activity. Although the mutation resulted in loss of a phosphorylation site in the activation loop of BRAF, it was predicted to increase BRAF kinase activity by mimicking an activating phosphorylation. CONCLUSIONS: This study, which reports a new BRAF mutation, highlights the usefulness of bioinformatic modeling in the prediction of functional effects of new mutations and indicates that mutation-specific screening tests might miss some rare BRAF mutations. These facts should be taken into consideration in the molecular diagnosis of thyroid cancer and in the design of therapeutic protocols based on inhibitors of the BRAF pathway.

Complications in thyroid surgery for carcinoma: one institution's surgical experience.

BACKGROUND: The purpose of this study was to evaluate the factors influencing morbidity after total thyroidectomy for carcinoma, such as the histotype, the extension of surgery, the primary surgery versus reoperation, and the surgeon's experience. METHODS: We performed a retrospective analysis on inferior laryngeal nerve (ILN) injury and permanent hypoparathyroidism (HPT) rates in 504 consecutive patients with thyroid carcinoma who were operated on by the same surgeon from 1999 to 2006. The following parameters were assessed at univariate analysis: histotype, total thyroidectomy with or without central node dissection (level VI), primary surgery versus reoperation, and early (group 1: 1999-2002, 143 patients) and late (group 2: 2003-2006, 361 patients) experience. RESULTS: The global incidence rates of ILN palsy and permanent HPT were 2.18% and 6.3%, respectively. The incidence of ILN damage after total thyroidectomy plus node dissection versus total thyroidectomy without node excision was 2.87% vs. 0.36% (p = 0.029). The incidence of permanent HPT in group 1 was 13.2% vs. 3.6% in group 2 (p = 0.0001). Moreover, the incidence rate of ILN palsy resulted higher in group 1 (2.8%) and in reoperation (3.4%), while the permanent HPT resulted higher in thyroidectomy with node dissection (6.8%) and reoperation (6.9%), although the difference was not significant. CONCLUSIONS: The complications after total thyroidectomy were progressively reduced as a result of a more accurate technique. Nevertheless, our study showed that the incidence of complications is mostly related to the dissection of central lymph node (level VI) and the surgeon's experience.