Activating FGFR1 Mutations in Sporadic Pheochromocytomas.

INTRODUCTION: Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with NF1 being the most common mutated gene (20-25%). In many sporadic tumors, however, a genetic explanation is still lacking. MATERIALS AND METHODS: We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas. RESULTS: We discovered on average 33 non-silent somatic variants per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pediatric brain tumors. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1-, RET,- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways. CONCLUSION: Besides RET and HRAS, FGFR1 is only the third protooncogene found to be recurrently mutated in pheochromocytomas. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of sporadic pheochromocytomas.

Impact of EMG Changes in Continuous Vagal Nerve Monitoring in High-Risk Endocrine Neck Surgery.

BACKGROUND: Continuous vagal intraoperative neuromonitoring (CIONM) of the recurrent laryngeal nerve (RLN) may reduce the risk of RLN lesions during high-risk endocrine neck surgery such as operation for large goiter potentially requiring transsternal surgery, advanced thyroid cancer, and recurrence. METHODS: Fifty-five consecutive patients (41 female, median age 61 years, 87 nerves at risk) underwent high-risk endocrine neck surgery. CIONM was performed using the commercially available NIM-Response 3.0 nerve monitoring system with automatic periodic stimulation (APS) and matching endotracheal tube electrodes (Medtronic Inc.). All CIONM events (decreased amplitude/increased latency) were recorded. RESULTS: APS malfunction occurred on three sides (3%). A total of 138 CIONM events were registered on 61 sides. Of 138, 47 (34%) events were assessed as imminent (13 events) or potentially imminent (34 events) lesions, whereas 91 (66%) were classified as artifacts. Loss of signal was observed in seven patients. Actions to restore the CIONM baseline were undertaken in 58/138 (42%) events with a median 60 s required per action. Four RLN palsies (3 transient, 1 permanent) occurred: one in case of CIONM malfunction, two sudden without any significant previous CIONM event, and one without any CIONM event. The APS vagus electrode led to temporary damage to the vagus nerve in two patients. CONCLUSIONS: CIONM may prevent RLN palsies by timely recognition of imminent nerve lesions. In high-risk endocrine neck surgery, CIONM may, however, be limited in its utility by system malfunction, direct harm to the vagus nerve, and particularly, inability to indicate RLN lesions ahead in time.

Post-PET ultrasound improves specificity of 18F-FDG-PET for recurrent differentiated thyroid cancer while maintaining sensitivity.

BACKGROUND: Positron emission tomography (PET) using fluor-18-deoxyglucose (18F-FDG) with or without computed tomography (CT) is generally accepted as the most sensitive imaging modality for diagnosing recurrent differentiated thyroid cancer (DTC) in patients with negative whole body scintigraphy with iodine-131 (I-131). PURPOSE: To assess the potential incremental value of ultrasound (US) over 18F-FDG-PET-CT. MATERIAL AND METHODS: Fifty-one consecutive patients with suspected recurrent DTC were prospectively evaluated using the following multimodal imaging protocol: (i) US before PET (pre-US) with or without fine needle biopsy (FNB) of suspicious lesions; (ii) single photon emission computed tomography (≥3 GBq I-131) with co-registered CT (SPECT-CT); (iii) 18F-FDG-PET with co-registered contrast-enhanced CT of the neck; (iv) US in correlation with the other imaging modalities (post-US). Postoperative histology, FNB, and long-term follow-up (median, 2.8 years) were taken as composite gold standard. RESULTS: Fifty-eight malignant lesions were identified in 34 patients. Forty lesions were located in the neck or upper mediastinum. On receiver operating characteristics (ROC) analysis, 18F-FDG-PET had a limited lesion-based specificity of 59% at a set sensitivity of 90%. Pre-US had poor sensitivity and specificity of 52% and 53%, respectively, increasing to 85% and 94% on post-US, with knowledge of the PET/CT findings (P < 0.05 vs. PET and pre-US). Multimodal imaging changed therapy in 15 out of 51 patients (30%). CONCLUSION: In patients with suspected recurrent DTC, supplemental targeted US in addition to 18F-FDG-PET-CT increases specificity while maintainin sensitivity, as non-malignant FDG uptake in cervical lesions can be confirmed.

Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study.

BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.

Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas.

Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bß, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.

Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective.

OBJECTIVE: This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). BACKGROUND: MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure. METHODS: Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B. RESULTS: All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%). CONCLUSIONS: MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.

Classification of aerodigestive tract invasion from thyroid cancer.

BACKGROUND: Widely invasive extrathyroidal thyroid cancer invading the aerodigestive tract (ADT) including larynx, trachea, hypopharynx, and/or esophagus occurs in 1-8 % of patients with thyroid cancer and is classified as T4a (current UICC/AJCC system). The T4a stage is associated with impaired tumor-free survival and increased disease-specific mortality. Concerning prognosis and outcome, further subdivisions of the T4a stage, however, have not been made so far. METHODS: This study is based on a systematic review of the relevant literature in the PubMed database. RESULTS: Retrospective studies suggest a better outcome in patients with invasion of the trachea or the esophagus when compared to laryngeal invasion. Regarding surgical strategies, ADT invasion can be classified based on a three-dimensional assessment determining surgical resection options. Regardless of the invaded structure, tumor infiltration of the ADT can be subdivided into superficial, deep extraluminal, and intraluminal invasion. In contrast to superficial ADT invasion, allowing tangential incomplete wall resection (shaving/extramucosal esophagus resection), deeper wall and intraluminal invasions require complete wall resection (either window or sleeve). Based on the Dralle classification (types 1-6), particularly airway invasion, can be further classified according to the vertical and horizontal extents of tumor invasion. CONCLUSIONS: The Dralle classification can be considered as a reliable subdivision system evaluated regarding surgical options as well as oncological outcome. However, further studies determining the prognostic impact of this technically oriented classification system are required.

Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease--a consensus statement of the European Society of Endocrine Surgeons (ESES).

PURPOSE: This "consensus statement" aims to summarise the current evidence-based knowledge as to "timing" and planning the "extent" of thyroid surgery in terms of an optimal balance between the prevention of thyroid malignancy (involving metastasis) and the risks associated with more extended surgery (permanent hypoparathyroidism, permanent paralysis of the recurrent laryngeal nerve). Surgery "in time" is influenced by genetic findings and age. Basal (and stimulated) calcitonin levels may individualise the timing and extent of surgery. MATERIALS AND METHODS: The review of English-language studies addressing the management of REarranged during Transfection proto-oncogene mutation carriers including the time, extent of thyroid surgery and results. Evidence is mostly obtained from well-designed, non-experimental descriptive investigations, such as comparative, correlation and case-control studies (level III) with a grading of recommendation B, or from expert committee reports or opinions and/or the clinical experience of respected authorities (level IV) with a grading of recommendation C, respectively. RESULTS: "Risk level D" includes multiple endocrine neoplasia 2B cases. Thyroidectomy is recommended within the first year of life, preferably as soon as possible, due to the very early transformation of C cell hyperplasia to more aggressive tumours. Calcitonin levels may be less helpful. In patients with codon 634 mutations (risk level C), thyroidectomy between ages 2 and 4 years has been proposed based upon evidence of age-dependent and codon-specific progression of early medullary thyroid cancer. In "risk level B" (codons 609, 611, 618, 620, 630 and 804), tandem mutation (804-778) patients should undergo thyroidectomy before the age of 6 years. "Risk level A" includes patients with mutations in codons 321, 515, 533, 600, 603, 606, 635, 649, 666, 768, 776, 790, 791, 804 (single mutation), 833, 844, 861, 891 or 912. Surgery may be postponed until the age of 10 years. However, postponing surgery and avoiding central (level VI) neck dissection in patients with risk levels A to C are only justified in families with a less aggressive MTC history and in combination with the results of basal (and calcium- or pentagastrin-stimulated) serum calcitonin levels. The moment of transition from C cell hyperplasia to MTC seems to occur when calcitonin levels rise. In patients with normal basal and stimulated calcitonin levels, the chance of micro-MTC increases significantly. CONCLUSIONS: Hereditary C cell disease acts as a model to apply the results of bedside genetic testing, age and calcitonin levels (genotype-age-calcitonin-concept) for the individual timing of thyroid surgery and its extent.

Latencies longer than 3.5 ms after vagus nerve stimulation does not exclude a nonrecurrent inferior laryngeal nerve.

BACKGROUND: It has recently been reported that a signal latency shorter than 3.5 ms after electrical stimulation of the vagus nerve signify a nonrecurrent course of the inferior laryngeal nerve. We present a patient with an ascending nonrecurrent inferior laryngeal nerve. In this patient, the stimulation latency was longer than 3.5 ms. CASE PRESENTATION: A 74-years old female underwent redo surgery due to a right-sided recurrent nodular goitre. The signal latency on electrical stimulation of the vagus nerve at the level of the carotid artery bifurcation was 3.75 ms. Further dissection revealed a nonrecurrent but ascending course of the inferior laryngeal nerve. Caused by the recurrent goitre, the nerve was elongated to about 10 cm resulting in this long latency. CONCLUSION: This case demonstrates that the formerly proposed "3.5 ms rule" for identifying a nonrecurrent course of the inferior laryngeal nerve has exceptions. A longer latency does not necessarily exclude a nonrecurrent laryngeal nerve.

High cardiac background activity limits 99mTc-MIBI radioguided surgery in aortopulmonary window parathyroid adenomas.

BACKGROUND: Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma. CASE PRESENTATION: Two female patients aged 72 (#1) and 79 years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370 MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985 mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced. CONCLUSION: High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma.

Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway.

BACKGROUND: Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway. METHODS: Twenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status. RESULTS: Ten out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type. CONCLUSIONS: KCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).

Latencies shorter than 3.5 ms after vagus nerve stimulation signify a nonrecurrent inferior laryngeal nerve before dissection.

OBJECTIVE: Quantitative electromyographic signals recorded after vagus nerve stimulation during intraoperative neuromonitoring (IONM) were analyzed for their clinical usefulness to identify and track a nonrecurrent inferior laryngeal nerve (NRLN) before dissection. BACKGROUND: A NRLN is anatomically shorter than a recurrent inferior laryngeal nerve (RLN). This disparity should cause differential latencies after vagus nerve stimulation during IONM, which may aid in distinguishing a NRLN from a RLN. Failure to identify a NRLN early on entails a great risk of nerve injury. METHODS: Included in this IONM case-control study were 18 cases with a NRLN and 36 controls with RLN anatomy matched for gender, age, body size, and underlying thyroid and parathyroid disease. RESULTS: All 18 NRLN were found in the right neck only. Cases with a NRLN had significantly shorter latencies than controls (medians of 2.7 vs. 4.6 ms; P < 0.001) but comparable amplitude and duration after stimulation of the right vagus nerve. With a latency threshold of <3.5 ms, sensitivity, specificity, positive and negative predictive value, and accuracy, respectively, were 100%, 94%, 100%, 97%, and 98% for diagnosis of a NRLN. CONCLUSIONS: A latency threshold of 3.5 ms after ipsilateral vagus nerve stimulation during IONM was able to discriminate well between a NRLN and a RLN in adults, helping avoid injury to the aberrant nerve. Additional studies should explore latency thresholds in children and adolescents who have shorter inferior laryngeal nerves and conceivably shorter latencies than adults.

No outcome differences between a laparoscopic and retroperitoneoscopic approach in synchronous bilateral adrenal surgery.

BACKGROUND: Two main approaches have been described for endoscopic adrenalectomy: the transperitoneal approach with the patient in the lateral decubitus position (LA) and the retroperitoneal approach with the patient in the prone position (ERA). The goal of the present study was to compare the results of LA and ERA for endoscopic bilateral synchronous adrenalectomy. PATIENTS AND METHODS: Between 1994 and 2008, 34 patients underwent bilateral synchronous adrenalectomy in two referral centers: 20 patients underwent LA in Pisa (group A), and 14 patients underwent ERA in Halle (group B). Sex, age, preoperative diagnosis, body mass index, preoperative medical treatments, diameter of glands, blood loss, operative time, complications, conversion, intensive care unit stay, day of first oral intake, length of postoperative recovery, histology report, and outcome were analyzed. RESULTS: There were 7 men and 13 women in group A and 6 men and 8 women in group B. Mean age was 48.1 years in group A and 38.9 years in group B. Body mass index was similar in the two groups. Diameters of the glands were larger in group A than in group B, at 61.1 versus 42.8 mm for the right side and 64.1 versus 37.4 mm for the left side. Mean hospital stay was longer in group B (8.2 versus 5.25 days; P = 0.002), whereas the intensive care unit stay was longer in group A (1.44 versus 1 day). CONCLUSIONS: It is not possible to determine which of the two approaches is better; both are feasible, safe, and effective and patient outcomes are almost the same.

Papillary thyroid cancer in children and adolescents does not differ in growth pattern and metastatic behavior.

OBJECTIVE: To provide comprehensive clinicopathologic data, comparing the growth pattern and metastatic behavior of papillary thyroid cancer between children and adolescents. STUDY DESIGN: This clinicopathologic investigation included 83 consecutive patients ages 6 to 18 years operated on for papillary thyroid cancer at a tertiary referral center in Germany (1994 to 2009). RESULTS: There was no difference in sex distribution, re-operation rate, medical history of external radiation, multifocal tumor growth, number of thyroid cancers, extrathyroidal tumor growth, lymph node metastasis, numbers of involved and removed nodes or distant metastasis among patients ages 6 to 11, 12 to 15, and 16 to 18 years. Patients with extrathyroidal growth, unlike those with intrathyroidal growth, had larger tumors, especially in the oldest age group (means of 20, 26, and 44 mm for patients ages 6 to 11, 12 to 15, and 16 to 18 years; P=.015); the statistical significance was lost after correction for multiple testing. CONCLUSION: Having comparable extent of disease, children should not undergo less extensive neck operations than adolescents for papillary thyroid cancer.

What are normal quantitative parameters of intraoperative neuromonitoring (IONM) in thyroid surgery?

PURPOSE: This study aimed at definition of normal quantitative parameters in intraoperative neuromonitoring during thyroid surgery. Only few and single center studies described quantitative data of intraoperative neuromonitoring. Definition of normal parameters in intraoperative neuromonitoring is believed to be a prerequisite for interpretation of results and intraoperative findings when using this method. Moreover, these parameters seem important in regard to the prognostic impact of the method on postoperative vocal cord function. MATERIAL AND METHODS: In a prospective multicenter study, quantitative analysis of vagal nerve stimulation pre- and postresection was performed in thyroid lobectomies. A standardized protocol determined set up and installation of neuromonitoring and defined assessment of quantitative parameters. Data of intraoperative neuromonitoring were respectively print-documented and centrally analyzed. RESULTS: In six participating centers a total of 1,289 patients with 1,996 nerves at risk underwent surgery for benign and malignant thyroid disease. Median amplitude was significantly larger for the right vs. left vagal nerve, latency was significantly longer for left vs. right vagal nerve and duration of the left vs. right vagal nerve significantly longer. Age disparities were only present in form of significantly higher amplitude in patients below 40 years; however, there is no continuous increase with age. Regarding gender, there was significantly higher amplitude and smaller latency in women compared to men. Duration of surgery revealed a reduction of amplitude with operative time; contrarily, latency and signal duration remained stable. The type of underlying thyroid disease showed no influence on quantitative parameters of intraoperative neuromonitoring. CONCLUSIONS: Systematic data of multicenter evaluation on quantitative intraoperative neuromonitoring parameters revealed differences between left and right vagal nerves in regard to amplitude, latency and duration of signal, gender, and age. The nature of thyroid disease showed no significant influence on quantitative parameters of intraoperative neuromonitoring. This study presents for the first time collective data of a large series of nerves at risk in a multicenter setting. It seems that definitions of "normal" parameters are prerequisite for the interpretation of quantitative changes of intraoperative neuromonitoring during thyroid surgery to enable interpretation of influence on surgical strategy and prediction of postoperative vocal cord function.

Management of lymph fistulas in thyroid surgery.

PURPOSE: Postoperative lymphatic leakage following thyroid surgery represents a management problem with considerate potential morbidity, psychological, and economical impact. Conservative and surgical management strategies for high- and low-output lymph fistulas are inconsistent. Reliable criteria to predict outcome of conservative versus surgical treatment in clinically evident lymph fistula are lacking. MATERIAL AND METHODS: A retrospective single-center chart review of consecutively quality-control-documented thyroid surgeries from January 1998 to December 2009 was performed to identify reported postoperative lymph fistulas. Documentation of surgical procedures, drainage, medical, and nutritional management was analyzed to identify risk factors for occurrence and criteria for management of evident lymph fistulas. RESULTS: There were 29 patients identified with postoperative clinical evidence of lymph fistulas following thyroid surgery; incidence was 0.5%. Indication to surgery comprised benign nodular goiter, recurrent nodular goiter, and thyroid carcinoma or local and lymphonodal carcinoma recurrences. There were 12 (41%) primary and 17 (59%) redo surgeries performed. Surgical procedures performed included thyroidectomy, completion thyroidectomy, and primary and redo central and lateral systematic microdissection of lymphatic compartments. All patients were initially submitted to fasting diet and medical treatment, successfully in 19 (66%), whereas ten (34%) patients underwent surgical intervention for fistula closure after failure of conservative treatment. Complications were one wound infection and fistula recurrence in five (26%) patients in the conservative group and two (20%) in the surgical group. Hospital stay was exceedingly prolonged in both groups with a median of 21 and 11 versus 6 days in patients with regular postoperative course following thyroid surgery. CONCLUSIONS: Data of this series support definition of the two categories of high- and low-output fistulas according to drainage collection with >300 versus <200 ml/day. Fasting in low-output fistula facilitates conservative treatment with closed drainage, whereas in high-output fistulas surgical intervention should be sought. Attendant criteria for treatment stratification are equally important, like patient's compliance, nutritional, and general health status as well as evidence for wound infection. Surgical closure of lymph fistula may be demanding when identification of the secreting fistula is limited and even muscle flap fortification may fail. Ultimately, in unsuccessfully reoperated fistula recurrences, open drainage may become necessary. Lymph fistulas cause significantly prolonged hospital stay, possible critical clinical decay, and unfavorable cosmetic and oncologic outcome while the superior management remains to be defined.

Familial nonmedullary thyroid carcinoma-clinical relevance and prognosis. A European multicenter study. ESES Vienna presentation.

PURPOSE: Approximately 5% of differentiated thyroid carcinomas are of familial origin. These familial nonmedullary thyroid carcinomas (FNMTC) have an increased risk of multifocal disease and lymph node involvement. Consequently, higher recurrence rates and decreased disease-specific survival rates are described. The best surgical approach is discussed controversially. PATIENTS AND METHODS: A survey among the international members of the German Society of Endocrine Surgeons revealed 20 families with two or more first-degree relatives with FNMTC. The mean age of the 41 patients (30 female, 11 male) with FNMTC was 40.6 years (18-73 years). RESULTS: Total thyroidectomy was performed in 31 of 41 patients (76%). Ninety-five percent of the tumors were papillary carcinomas. Two of 41 patients had follicular carcinomas. Ten patients (24%) with papillary carcinomas were diagnosed with Hashimoto's thyroiditis. The mean tumor size was 1.45 cm. FNMTC was multifocal in 12 patients (29%). A systematic lymph node dissection was performed in 21 of 41 patients (51%). Lymph nodes metastases were found in seven of these 21 patients. Twenty-eight of the patients (68%) underwent postoperative radioiodine ablation. After a mean follow-up of 7.2 years, 39 patients (95%) were disease free. One patient developed local recurrence and lung metastases, 10 and 25 years, respectively, after initial diagnosis. Another patient died 2 years postoperatively from advanced metastatic disease. CONCLUSIONS: FNMTC is associated with an early onset of small, mostly papillary thyroid carcinomas and an increased risk of multifocality and lymph node involvement. Total thyroidectomy and systematic neck dissection are recommended together with radioiodine ablation. Screening for first-degree relatives should start at age 18 years.

Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies.

The identification of high-risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging. Our study was conducted to analyze whether the quantification of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator receptor (u-PAR) and transcription factor binding to the u-PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors. Tumor/normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas (papillary, medullary, follicular and anaplastic, PTC, MTC, FTC and ATC) or follicular adenomas. U-PAR, MMP-1, MMP-7 and MMP-9 amounts were determined by ELISA, and transcription factor binding was determined by electrophoretic mobility shift assay. Binding of transcription factors to the u-PAR promoter was observed, but not associated with u-PAR expression. Carcinomas except MTC expressed significantly more u-PAR/MMPs than adenomas/normal tissues, this being associated with advanced pT- or M-stages. MMP-1 and MMP-9 were significantly higher in follicular carcinomas than in adenomas. In carcinomas, high u-PAR-gene expression correlated significantly with high MMP-9, the latter being associated with MMP-7 in normal tissues. Poor survival in differentiated tumors was associated in trend (p = 0.07); poor survival of all patients (p = 0.043) and especially of patients with carcinomas of follicular origin (including ATC), but not medullary carcinomas, were significantly associated with high u-PAR-protein (p = 0.015). Quantification of u-PAR is of prognostic relevance in thyroid carcinomas of non-c-cell origin, and u-PAR in part may be regulated nontranscriptionally in thyroid cancers. This is the first study to suggest MMP-1/-9 as significant differentiation markers between follicular adenoma and follicular carcinoma.

Germ-line mutations in nonsyndromic pheochromocytoma.

BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.