A Thyroid Genetic Classifier Correctly Predicts Benign Nodules with Indeterminate Cytology: Two Independent, Multicenter, Prospective Validation Trials.

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.

Estudio y manejo de nódulos tiroideos por médicos no especialistas. Consenso SOCHED / Study and management of thyroid nodes by non specialist physicians: SOCHED consensus

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.

A 10-Gene Classifier for Indeterminate Thyroid Nodules: Development and Multicenter Accuracy Study.

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.

Importancia de la tiroglobulina sérica preablativa en la predicción de sobrevida libre de enfermedad en cáncer diferenciado de tiroides / Preablative serum thyroglobulin as predictor of disease-free survival in differentiated thyroid cancer

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.

[Preablative serum thyroglobulin as predictor of disease-free survival in differentiated thyroid cancer]. / Importancia de la tiroglobulina sérica preablativa en la predicción de sobrevida libre de enfermedad en cáncer diferenciado de tiroides.

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.

Paragangliomas múltiples asociados a mutación del gen SDHB: Caso clínico / Multiple paragangliomas associated to a SDHB gene mutation: Report of one case

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 dehydroge-nase 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 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).

Insuficiencia suprarrenal y crisis addisoniana como primera manifestación de cáncer de pulmón y metástasis suprarrenal bilateral: Caso clínico / Addisonian crisis caused by metastatic lung cancer: Report of one case

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.

Síndrome de carcinoide con manifestación inicial a nivel valvular cardíaco: a raíz de un caso clínico / Carcinoid syndrome presenting as valvular diseas: report of one case

Carcinoid syndrome is observed in one third of carcinoid tumors and usually appears when there are liver metastases. One of the main complications of this syndrome is the appearance of tricuspid or pulmonary valvular disease. We report a 56 years old male presenting with malaise and a weight loss of 10 kg. On physical examination, a heart murmur suspicious of a double tricuspid lesion was found. The echocardiogram was suggestive of a carcinoid valvular disease. The abdominal CAT scan showed a small bowel tumor. Urinary 5-hydroxy-indol- acetic acid values were highly elevated. The patient was subjected to excision of the distal ileum, liver metastasectomy and hemicolectomy. The pathological study of the surgical piece confirmed the diagnosis of carcinoid tumor. Two years after surgery, the patient is in stable conditions.

[Multiple paragangliomas associated to a SDHB gene mutation: report of one case]. / Paragangliomas múltiples asociados a mutación del gen SDHB: Caso clínico.

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 caused by metastatic lung cancer. Report of one case]. / Insuficiencia suprarrenal y crisis addisoniana como primera manifestación de cáncer de pulmón y metástasis suprarrenal bilateral. Caso clínico.

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.

[Thyroglobulin levels in needle lymph node cytology for the detection of papillary thyroid cancer recurrence]. / Utilidad de la detección de tiroglobulina en el aspirado de punción ganglionar cervical en el seguimiento de pacientes con cancer papilar de tiroides.

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.

Utilidad de la detección de tiroglobulina en el aspirado de punción ganglionar cervical en el seguimiento de pacientes con cancer papilar de tiroides / Thyroglobulin levels in needle lymph node cytology for the detection of papillary thyroid cancer recurrence

Background: During the detection ofneck 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 sean 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 aecuracy 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 metástasis 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 percent for LTg and 56.2 percent for cytology. We identified byLTg 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 metástasis. This method is useful even in the presence ofsAbTg.

[Results of treatment for acromegaly in 53 patients: it is time of intervention]. / Resultados terapéuticos en pacientes acromegálicos: es tiempo de intervenir.

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.