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Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77–97] and 91% [95% CI 79–98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82–94] and 87% [95% CI 77–94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

Background: In most of the world, diagnostic surgery remains the most frequent approach for indeterminate thyroid cytology. Although several molecular tests are available for testing in centralized commercial laboratories in the United States, there are no available kits for local laboratory testing. The aim of this study was to develop a prototype in vitro diagnostic (IVD) gene classifier for the further characterization of nodules with an indeterminate thyroid cytology. Methods: In a first stage, the expression of 18 genes was determined by quantitative polymerase chain reaction (qPCR) in a broad histopathological spectrum of 114 fresh-tissue biopsies. Expression data were used to train several classifiers by supervised machine learning approaches. Classifiers were tested in an independent set of 139 samples. In a second stage, the best classifier was chosen as a model to develop a multiplexed-qPCR IVD prototype assay, which was tested in a prospective multicenter cohort of fine-needle aspiration biopsies. Results: In tissue biopsies, the best classifier, using only 10 genes, reached an optimal and consistent performance in the ninefold cross-validated testing set (sensitivity 93% and specificity 81%). In the multicenter cohort of fine-needle aspiration biopsy samples, the 10-gene signature, built into a multiplexed-qPCR IVD prototype, showed an area under the curve of 0.97, a positive predictive value of 78%, and a negative predictive value of 98%. By Bayes' theorem, the IVD prototype is expected to achieve a positive predictive value of 64–82% and a negative predictive value of 97–99% in patients with a cancer prevalence range of 20–40%. Conclusions: A new multiplexed-qPCR IVD prototype is reported that accurately classifies thyroid nodules and may provide a future solution suitable for local reference laboratory testing.

The thyroid nodule is a frequent cause of primary care consultation. The prevalence of a palpable thyroid nodule is approximately 4-7%, increasing up to 67% by the incidental detection of nodules on ultrasound. The vast majority are benign and asymptomatic, staying stable over time. The clinical importance of studying a thyroid nodule is to exclude thyroid cancer, which occurs in 5 to 10% of the nodules. The Board of SOCHED (Chilean Society of Endocrinology and Diabetes) asked the Thyroid Study Group to develop a consensus regarding the diagnostic management of the thyroid nodule in Chile, aimed at non-specialist physicians and adapted to the national reality. To this end, a multidisciplinary group of 31 experts was established among university academics, active researchers with publications on the subject and prominent members of scientific societies of endocrinology, head and neck surgery, pathology and radiology. A total of 14 questions were developed with key aspects for the diagnosis and subsequent referral of patients with thyroid nodules, which were addressed by the participants. In those areas where the evidence was insufficient or the national reality had to be considered, the consensus opinion of the experts was used through the Delphi methodology. The consensus was approved by the SOCHED board for publication.

RESUMENLas técnicas de laboratorio de análisis hormonales han experimentado grandes progresos en las últimas décadas, actualmente se pueden realizar determinaciones hormonales con gran precisión y automatización, sin embargo, existen muchos elementos que es necesario tener en consideración al momento de interpretar un examen hormonal. El elegir el examen adecuado para la condición que estamos estudiando, el conocer sus limitaciones y potenciales falsos positivos y negativos es parte del conocimiento que es fundamental tener como clínicos. En este artículo se pretende entregar una breve revisión de las principales determinaciones hormonales, orientado a aspectos que puedan ser de utilidad al médico no especialista en su práctica clínica.SUMMARYHormonal assays have achieved great progress in recent decades, currently hormonal tests can be performed with high accuracy and automation, but there are many issues that must be taken into account when we interpretate a hormone test. Choosing the right test for the condition that we are studying, knowing its limitations and potential false positive and negative is part of the knowledge that as clinicians we face. In this article, we give a brief review of the main hormonal determinations oriented to non-specialist physicians considering practical aspects that may be useful in their clinical practice.

Background: Serum thyroglobulin (sTg) is an excellent marker of persistence or recurrence of disease in differentiated thyroid cancer (DTC), however its role as prognostic factor has not been fully established. Aim: To assess the value of the preablative thyroglobulin (pTg) as predictor of disease-free survival in DTC. Patients and Methods: Retrospective study of 104 patients with low and intermediate risk DTC subjected to total thyroidectomy and 131iodine ablation. TSH, pTg and thyroglobulin antibodies (AbTg) were determined by chemiluminescence. Patients with distant metastases or presence of AbTg were excluded. Results were analyzed using receiving operating characteristic (ROC) curves. Results: During the 40 ± 29 months of follow-up (range 6-132), 14 of 104 (13%) patients had recurrence of disease. pTg was an independent indicator to predict disease-free survival. Using a pTg cutoff of < 10 ng/ml the negative predictive value was 99%, sensitivity 93%, specificity 82%, positive likelihood ratio (LR) 5.2 and negative LR 0,087. Conclusions: pTg value is useful as a prognostic marker in predicting disease-free survival in DTC patients with low or intermediate risk of recurrence.

Addisonian crisis as a first manifestation of metastatic disease secondary to cancer is uncommon. We report a 63-year-old man with a history of one year of fatigue, weakness, weight loss and repeated symptomatic hypoglycemia. The cortisol stimulation test with ACTH confirmed primary adrenal insufficiency. While receiving adequate treatment with oral hydrocortisone, he presented an adrenal crisis that was treated properly. A CT scan of the lung demonstrated a nodule in the upper right lobe and bilateral adrenal tumors. The biopsy of the lesion revealed a lung adenocarcinoma. The staging with positron emission tomography using 18 fluoroglucose (PET/CT18F- FDG) showed hypermetabolic uptake in the primary lung tumor and in both adrenal glands, suggesting metastatic implants.

Serum thyroglobulin (sTg) is an excellent marker of persistence or recurrence of disease in differentiated thyroid cancer (DTC), however its role as prognostic factor has not been fully established.To assess the value of the preablative thyroglobulin (pTg) as predictor of disease-free survival in DTC.Retrospective study of 104 patients with low and intermediate risk DTC subjected to total thyroidectomy and 131iodine ablation. TSH, pTg and thyroglobulin antibodies (AbTg) were determined by chemiluminescence. Patients with distant metastases or presence of AbTg were excluded. Results were analyzed using receiving operating characteristic (ROC) curves.During the 40 ± 29 months of follow-up (range 6-132), 14 of 104 (13%) patients had recurrence of disease. pTg was an independent indicator to predict disease-free survival. Using a pTg cutoff of10 ng/ml the negative predictive value was 99%, sensitivity 93%, specificity 82%, positive likelihood ratio (LR) 5.2 and negative LR 0,087.pTg value is useful as a prognostic marker in predicting disease-free survival in DTC patients with low or intermediate risk of recurrence.

Paragangliomas are tumors arising from sympathetic and parasympathetic tissues. The classic associated syndromes are neurofibromatosis type 1, multiple endocrine neoplasia type 2 and von Hippel-Lindau. Germline mutations of succinate dehydrogenase subunits genes, are associated with familial paraganglioma syndromes 1,2,3 and 4. We report a 29-year-old woman with a family background of pheochromocytoma and history of paroxysmal headache, nausea, sweating, palpitations, associated with severe hypertension. The patient had elevated plasma noradrenalin and urinary normetanephrines. Imaging studies revealed three retroperitoneal extra-adrenal masses. The clinical and laboratory study of classic syndromes associated with paraganglioma was negative. The patient was operated and the pathological study of the surgical specimen was consistent with paragangliomas. The genetic study showed a mutation in the SDHB succinate dehydrogenase gen, Exon 2 of CCTCA c.300_304 (p.P56delYfsX5).

Addisonian crisis as a first manifestation of metastatic disease secondary to cancer is uncommon. We report a 63-year-old man with a history of one year of fatigue, weakness, weight loss and repeated symptomatic hypoglycemia. The cortisol stimulation test with ACTH confirmed primary adrenal insufficiency. While receiving adequate treatment with oral hydrocortisone, he presented an adrenal crisis that was treated properly. A CT scan of the lung demonstrated a nodule in the upper right lobe and bilateral adrenal tumors. The biopsy of the lesion revealed a lung adenocarcinoma. The staging with positron emission tomography using 18 fluoroglucose (PET/CT18F- FDG) showed hypermetabolic uptake in the primary lung tumor and in both adrenal glands, suggesting metastatic implants.

Paragangliomas are tumors arising from sympathetic and parasympathetic tissues. The classic associated syndromes are neurofi bromatosis type 1, multiple endocrine neoplasia type 2 and von Hippel-Lindau. Germline mutations of succinate dehydroge-nase subunits genes, are associated with familial paraganglioma syndromes 1, 2, 3 and 4. We report a 29-year-old woman w ith a family background of pheochromocytoma and history of paroxysmal headache, nausea, sweating, palpitations, associated with severe hypertension. The patient had elevated plasma noradrenalin and urinary normetanephrines. Imaging studies revealed three retroperitoneal extra-adrenal masses. The clinical and laboratory study of classic syndromes associated with para-ganglioma was negative. The patient was operated and the pathological study of the surgical specimen was consistent with paragangliomas. The genetic study showed a mutation in the SDHB succinate dehydrogenase gen, Exon 2 of CCTCA c.300_304 (p.P56delYfsX5). (Rev Med Chile 2011; 139: 1475-1480).

During the detection of neck recurrence in patients with Papillary Thyroid Carcinoma (PTC), sometimes it is difficult to distinguish metastatic from inflammatory neck lymph nodes. The measurement of serum thyroglobulin (sTg) under thyroid hormone suppression therapy the presence of serum thyroglobulin antibodies (sAbTg), the diagnostic whole body scan and cytology can give false negative results. Measurement of thyroglobulin in the washout fluid from fine-needle aspiration biopsy (FNAB) of suspicious neck lymph nodes could improve the diagnostic accuracy.To evaluate the usefulness of detecting Tg in lymph nodes (LTg) suspicious by ultrasonography (US) and compare it to cytology.Between the years 2004 and 2007 we prospectively studied 30 patients with PTC and cervical US findings of suspicious recurrence. LTg was assayed in US guided FNAB used for cytology.Sixteen out of 30 patients underwent surgery using as selective criteria an LTg higher than sTg or a positive cytology. Surgery confirmed the presence of metastasis in all 15 patients with positive LTg (8 with positive cytology) and in 1 patient with negative LTg and positive cytology (a case with undifferentiated thyroid cancer). The sensitivity was 93.7% for LTg and 56.2% for cytology. We identified by LTg 3 of 6 patients with undetectable sTg and positive sAbTg.The presence of LTg showed a higher sensitivity than cytology for the detection of cervical lymph node metastasis. This method is useful even in the presence of sAbTg.

Background: During the detection of neck recurrence in patients with Papillary Thyroid Carcinoma (PTC), sometimes it is difficult to distinguish metastatic from inflammatory neck lymph nodes. The measurement of serum thyroglobulin (sTg) under thyroid hormone suppression therapy, the presence of serum thyroglobulin antibodies (sAbTg), the diagnostic whole body scan and cytology can give false negative results. Measurement of thyroglobulin in the washout fluid from fine-needle aspiration biopsy (FNAB) of suspicious neck lymph nodes could improve the diagnostic accuracy. Aim: To evaluate the usefulness of detecting Tg in lymph nodes (LTg) suspicious by ultrasonography (US) and compare it to cytology. Patients and Methods: Between the years 2004 and 2007 we prospectively studied 30 patients with PTC and cervical US findings of suspicious recurrence. LTg was assayed in US guided FNAB used for cytology. Results: Sixteen out of 30 patients underwent surgery using as selective criteria an LTg higher than sTg or a positive cytology. Surgery confirmed the presence of metastasis in all 15 patients with positive LTg (8 with positive cytology) and in 1 patient with negative LTg and positive cytology (a case with undifferentiated thyroid cancer). The sensitivity was 93.7% for LTg and 56.2% for cytology. We identified by LTg 3 of 6 patients with undetectable sTg and positive sAbTg. Conclusions: The presence of LTg showed a higher sensitivity than cytology for the detection of cervical lymph node metastasis. This method is useful even in the presence of sAbTg (Rev Med Chile 2008; 136: 1107-12). (Key words: Biopsy, fine-needle; Neoplasm metastasis; Thyroid neoplasms)

Lingual thyroid is a rare developmental disorder and is more frequent in women. The pathogenesis is unclear but may be related to the presence of maternal blocking autoantibodies against the thyroid. Treatment of this disorder includes the use of levothyroxine in order to correct the hypothyroidism, which is very frequent and to induce the shrinkage of the gland. When symptoms of obstruction or bleeding appear, ablative therapy by means of surgery or radioiodine is warranted. We report three cases and discuss the approach to diagnosis and a strategy for management.

The treatment of choice for acromegaly is surgery that, according to the literature, is curative in 91% of pituitary microadenomas and 73% of macroadenomas.To report the results of surgical treatment in 53 patients with acromegaly.Retrospective review of medical records of all patients with acromegaly, operated between 1984 and 2004. When necessary, patients were contacted by telephone to complete information or to perform biochemical or imaging studies. A normal value of insulin like growth factor I (IGF-1) for age and sex, a growth hormone (GH) nadir of less than 1 ng/ml during a glucose tolerance test or a basal GH of less than 2.5 ng/ml, all assessed three months after surgery, were considered as criteria for cure.Biochemical cure was achieved in 67% of patients with pituitary microadenomas and 21% of patients with macroadenomas. In 47% of patients with neuro-ophtalmological involvement, a partial or total recovery in the visual field defect was achieved. The most common surgical complications were transient diabetes insipidus in 19%, persistent diabetes insipidus in 4% and cerebrospinal fluid fistula in 4%. A lower size of the tumor and lower preoperative growth hormone levels were associated with a better chance of cure.The cure rates obtained in this group of patients are clearly lower than those reported abroad. These results stress the importance of having a national registry of acromegaly and the need to train neurosurgeons in the treatment of pituitary tumors.

Background: The treatment of choice for acromegaly is surgery that, according to the literature, is curative in 91% of pituitary microadenomas and 73% of macroadenomas. Aim: To report the results of surgical treatment in 53 patients with acromegaly. Material and methods: Retrospective review of medical records of all patients with acromegaly, operated between 1984 and 2004. When necessary, patients were contacted by telephone to complete information or to perform biochemical or imaging studies. A normal value of insulin like growth factor I (IGF-1) for age and sex, a growth hormone (GH) nadir of less than 1 ng/ml during a glucose tolerance test or a basal GH of less than 2.5 ng/ml, all assessed three months after surgery, were considered as criteria for cure. Results: Biochemical cure was achieved in 67% of patients with pituitary microadenomas and 21% of patients with macroadenomas. In 47% of patients with neuro-ophtalmological involvement, a partial or total recovery in the visual field defect was achieved. The most common surgical complications were transient diabetes insipidus in 19%, persistent diabetes insipidus in 4% and cerebrospinal fluid fistula in 4%. A lower size of the tumor and lower preoperative growth hormone levels were associated with a better chance of cure. Conclusions: The cure rates obtained in this group of patients are clearly lower than those reported abroad. These results stress the importance of having a national registry of acromegaly and the need to train neurosurgeons in the treatment of pituitary tumors (Rev Méd Chile 2006; 134: 989-96).

We report a 35 years old female with left lobe thyroid hemiagenesis who initially was euthyroid and then developed hyperthyroidism due to Graves disease. Hemiagenesis of the thyroid gland is a rare anomaly with an uncertain incidence; up to now 256 cases have been reported. The detection is often made by either clinical symptoms of thyroid dysfunction, by imaginological studies or surgical/pathological procedures. No explanation has been given for the development of this anomaly; left lobe aplasia and predominance of occurrence in women have been most frequently reported. (Rev Med Chile 2000; 128: 896-8).

Multiple endocrine neoplasias (MEN) are syndromes inherited as autosomal dominant. The application of the techniques of molecular biology has made possible the identification of the genes causing MEN 1 and 2. The gene responsable for MEN 1 belongs to the family of tumor suppressor genes and encodes for a protein named MENIN whose function remains to be elucidated. The identification of mutant MEN 1 gene carriers who are at risk of developing this syndrome requires frequent biochemical screening for the development of endocrine tumors. MEN 2 is a consequence of mutations in the Ret proto- oncogene (c-Ret). This gene encodes for a tyrosine kinase receptor thought to play a role in the development of neural crest- derived tissue. Members of kindred with either MEN 2A or MEN 2B should be screened by direct DNA testing early in life for mutations in c-Ret. Those with the mutation should be advised to have thyroidectomy at five years of age in children with MEN 2A and earlier in children with MEN 2B . Some cases of sporadic MTC are actually MEN 2A or Familial MTC after c-Ret testing is done, therefore routine application of this test is recommended in all cases of apparent sporadic MTC (Rev Med Chile 2000; 128: 811-20).

Background: To stabilize Graves disease and deplete the preformed hormone, the use of antithyroid drugs prior 131I therapy has been suggested, specially in those patients with severe thyrotoxicosis and in the elderly. However, PTU may reduce the effectiveness of 131I. Aim: To study the effects of PTU pretreatment before 131I administration. Subjets and methods: A retrospective analysis of the medical records of patients with Graves disease treated with 131I from 1989 to 1997 was made. Of 244 patients with adequate follow-up for at least 12 months after 131I treatment, 142 had not been pretreated and 102 had received PTU prior to 131I therapy. Pretreated patients were distributed according to the number of days that PTU was discontinued before reciving 131I, forming four groups (a=5d, b=6-14 d, c=15-30 d and d=31-60 d). Radioiodine was delivered according to our protocol of 120 µCi per gram of thyroid tissue, as estimated by clinical examination. Therapy was considered successful when laboratory evidence of euthyroidism or hypothyroidism after one year of treatment was obtained and as a failure when undetectable TSH values persisted after 12 months of treatment with 131I. Results: All groups were comparable as to age, gender, goiter size, and 24 h radioiodine uptake. Control of hyperthyroidism was achieved in 76% of the non pretreated group. A similar percentage was observed in groups (b), (c) and (d). However, the disease was controlled in only 50% of group (a) patients (p