Rosa Paula M. Biscolla

One Month Is Sufficient for Urinary Iodine to Return to Its Baseline Value After the Use of Water-Soluble Iodinated Contrast Agents in Post-Thyroidectomy Patients Requiring Radioiodine Therapy

BACKGROUND There is a concern regarding the use of iodinated contrast agents (ICA) for chest and neck computed tomography (CT) to localize metastatases in patients with differentiated thyroid cancer (DTC). This is because the iodine in ICA can compete with (131)I and interfere with subsequent whole scans or radioactive iodine treatment. The required period for patients to eliminate the excess iodine is not clear. Therefore, knowing the period for iodine levels to return to baseline after the injection of ICA would permit a more reliable indication of CT for DTC patients. The most widely used marker to assess the plasmatic iodine pool is the urinary iodine (UI) concentration, which can be collected over a period of 24 hours (24U) or as a single-spot urinary sample (sU). As 24U collections are more difficult to perform, sU samples are preferable. It has not been established, however, if the measurement of iodine in sU is accurate for situations of excess iodine. METHODS We evaluated 25 patients with DTC who received ICA to perform chest or neck CT. They collected 24U and sU urinary samples before the CT scan and 1 week and 1, 2, and 3 months after the test. UI was quantified by a semiautomated colorimetric method. RESULTS Baseline median UI levels were 21.8 μg/dL for 24U and 26 μg/dL for sU. One week after ICA, UI median levels were very high for all patients, 800 μg/dL. One month after ICA, however, UI median levels returned to baseline in all patients, 19.0 μg/dL for 24U and 20 μg/dL for sU. Although the values of median UI obtained from sU and 24U samples were signicantly different, we observed a significant correlation between samples collected in 24U and sU in all evaluated periods. CONCLUSION One month is required for UI to return to its baseline value after the use of ICA and for patients (after total thyroidectomy and radioiodine therapy) to eliminate the excess of iodine. In addition, sU samples, although not statistically similar to 24U values, can be used as a good marker to evaluate patients suspected of contamination with iodine.

Diagnóstico de metástases de carcinoma papilífero de tiróide através da dosagem de tiroglobulina no líquido obtido da lavagem da agulha utilizada na punção aspirativa

The widespread use of neck ultrasonography (US) during the follow-up of patients with papillary thyroid carcinoma (PTC) has led to the discovery of small cervical lymph nodes (LN). Although US has a high sensitivity for diagnosing LN, fine needle aspiration biopsy (FNA) and measurement of thyroglobulin in fine needle aspirates (FNA-Tg) have proven to be invaluable tools. The aim of this study is to determine the sensitivity of the combined use of neck US, FNA biopsy and FNA-Tg for diagnosis of cervical lymph nodes. We have studied 32 patients with 44 LN detected by US, 19 classified as inflammatory and 25 as suspicious. 15 of those 25 suspicious LN had high FNA-Tg (13 of the 15 had positive cytology and 2 indeterminate). All of these 15 LN (11 patients) were proven to be PTC metastasis by histopathology. All 19 inflammatory LN and those 10/25 suspicious LN, had cytology negative for malignancy and undetectable FNA-Tg. We conclude that fine needle aspiration biopsy and FNA-Tg combined with neck US are essential for detecting positive cervical lymph nodes due to its high sensitivity and specificity and it should be considered the standard for investigating locally recurrent disease in patients with PTC.

Early Diagnosis of Multiple Endocrine Neoplasia Type 2B: a Challenge for Physicians

BACKGROUND The hereditary form of medullary thyroid carcinoma may occur isolated as a familial medullary thyroid carcinoma (FMTC) or as part of Multiple Endocrine Neoplasia 2A (MEN2A) and 2B (MEN2B). MEN2B is a rare syndrome, its phenotype may usually, but not always, be noted by the physician. In the infant none of the MEN2B characteristics are present, except by early gastrointestinal dysfunction caused by intestinal neuromas. When available, genetic analysis confirms the diagnosis and guides pre-operative evaluation and extent of surgery. Here we report four cases of MEN2B in which the late diagnosis had a significant impact in clinical evolution and, potentially, in overall survival. CASE REPORT We report four cases, 2 men and 2 women, with differences in their phenotypes and with a late diagnosis. The first case has a history of severe gastrointestinal obstruction requiring a surgery intervention two days after his birth. The second told had nodules in the oral mucosa and constipation since childhood. The third case referred a history of constipation from birth until 5 months of life. The fourth has had a history of chronic constipation since childhood. DISCUSSION New concepts have emerged since the RET oncogene was identified in 1993 as the responsible gene for hereditary medullary thyroid carcinoma. The majority of MEN2B individuals have M918T mutation in the exon 16 of RET, with a few cases having a mutation A883F or the association of V804M with E805K, Y806C or S904C mutations. The consensus classifies the RET mutation in codon 918 as of highest risk and recommends total thyroidectomy and central lymph node dissection until 6 months after birth. A fast and precise diagnosis is essential to reach these goals. The identification of early manifestations such as intestinal ganglioneuromatosis and oral mucosal neuromas should prompt the physician to initiate an investigation for multiple endocrine neoplasia type 2B. CONCLUSION The diagnosis of MEN2B is very important to allow appropriate investigation of associated diseases and to allow counseling and appropriate screening of relatives for a RET mutation. Even patients with MEN2B, which often have typical physical features, may not be properly recognized and be followed as a sporadic case. Based on this, all suspicious cases of multiple endocrine neoplasia should undergo a molecular genetic test.

Expanding Indications for Recombinant Human TSH in Thyroid Cancer

On December 17, 2007, Genzyme Corporation (Cambridge, MA) announced that the U.S. Food and Drug Administration (FDA) had approved a supplemental indication for Thyrogen®, its brand of recombinant human thyroid-stimulating hormone (rhTSH), to be used in combination with radioiodine to ablate, or destroy, the remaining thyroid tissue in patients who have had surgery for differentiated thyroid cancer. Although rhTSH was first approved for clinical use in the United States, most European and certain Asian and South American countries approved rhTSH for ablation of postsurgical thyroid remnants before the FDA action. In this article we review the timelines for rhTSH approval and present the views of experts from around the world regarding the expanding indications for rhTSH in thyroid cancer.* The commentary concludes with an editorial summary. Timelines for rhTSH Approval† On November 30, 1998, the FDA issued its first approval of rhTSH, as “an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with thyroid cancer” (1). In the original approval, provisions were made for thyroid cancer patients who were unable to mount an endogenous TSH response to hypothyroidism, such as those with pituitary failure. On September 3, 2000, rhTSH was approved in European Union countries‡ for preparation of Tg testing with or without radioiodine imaging for detection of thyroid remnants and well-differentiated thyroid cancer in adult postthyroidectomy patients maintained on hormone suppression therapy. Low-risk patients with well-differentiated thyroid carcinoma who have undetectable serum Tg levels on thyroid hormone suppression could be followed by assaying rhTSH-stimulated serum Tg levels. These indications were adopted in a similar time period by Liechtenstein, Norway, and Iceland, and similar indications were approved by Ukraine on May 17, 2004. On February 23, 2005, rhTSH was approved in Europe for pretherapeutic stimulation and low-risk postthyroidectomy adult patients maintained on hormone suppression therapy for the ablation of thyroid remnant tissue in combination with 3.7 GBq (100 mCi) radioactive iodine (RAI). In Australia (2006), Malaysia (2007), Thailand (2007), and Singapore (2007), government agencies approved indications for rhTSH similar to that adapted by the FDA in 2007. As noted by Dr. Yamashita, rhTSH has not been approved for clinical use in Japan. Prior to the approval of rhTSH for remnant ablation in 2007, the FDA approved label changes on March 11, 2004, and January 1, 1006. These dealt with Thyrogen® Tg testing alone and in combination with radioiodine imaging in patients with metastatic disease and a Quality of Life statement, respectively. In 2006 rhTSH was approved for clinical use by many countries in South America (see below).

Measurement of calcitonin and calcitonin gene-related peptide mRNA refines the management of patients with medullary thyroid cancer and may replace calcitonin-stimulation tests.

BACKGROUND Serum calcitonin (sCT) is the main tumor marker for medullary thyroid cancer (MTC), but it has certain limitations. Various sCT assays may have important intra-assay or interassay variation and may yield different and sometimes conflicting results. A pentagastrin- or calcium-stimulation calcitonin (CT) test may be desirable in some situations. Alternatively, or in the absence of the stimulation test, mRNA detection offers the advantages of being more comfortable and less invasive; it only requires blood collection and has no side effects. The objective of this study was to investigate the applicability of measuring calcitonin-related polypeptide alpha (CALCA) gene transcripts (CT-CALCA and calcitonin gene-related peptide [CGRP]-CALCA) in patients with MTC and in relatives diagnosed with a RET mutation and to test mRNA as an alternative diagnostic tool for the calcitonin-stimulation test. METHODS Twenty-three healthy controls and 26 individuals evaluated for MTC were selected, including patients with sporadic or hereditary MTC and RET mutation-carrying relatives. For molecular analysis, RNA was extracted from peripheral blood, followed by cDNA synthesis using 3.5 μg of total RNA. Quantitative real-time polymerase chain reaction (RT-qPCR) was performed with SYBR Green and 200 nM of each primer for the two specific mRNA targets (CT-CALCA or CGRP-CALCA) and normalized with the ribosomal protein S8 as the reference gene. RESULTS We detected CALCA transcripts in the blood samples and observed a positive correlation between them (r=0.946, p<0.0001). Both mRNAs also correlated with sCT (CT-CALCA, r=0.713, p<0.0001; CGRP-CALCA, r=0.714, p<0.0001). The relative expression of CT-CALCA and CGRP-CALCA presented higher clinical sensitivity (86.67 and 100, respectively), specificity (97.06 and 97.06), positive predictive value (92.86 and 93.75), and negative predictive value (94.29 and 100), than did sCT (73.33, 82.35, 64.71, and 87.50, respectively). In addition, the CALCA transcript measurement mirrored the response to the pentagastrin test. CONCLUSION We demonstrate that the measurement of CALCA gene transcripts in the bloodstream is feasible and may refine the management of patients with MTC and RET mutation-carrying relatives. We propose considering the application of this diagnostic tool as an alternative to the calcitonin-stimulation test.

Lithium as an adjuvant in the postoperative ablation of remnant tissue in low-risk thyroid carcinoma.

BACKGROUND Thyroid remnant ablation (RA) with 30 mCi of radioactive iodine (131I) in patients thyroidectomized for treatment of low-risk differentiated thyroid carcinoma (DTC) has a success rate of 64% to 84%. Lithium increases the residence time of 131I in the thyroid tissue. The aim of this study was to determine if lithium treatment added to 30 mCi 131I would enhance the success rate of this treatment compared with 30 mCi 131I alone in patients who were thyroidectomized for treatment of low-risk DTC. METHODS This was a randomized study with endpoint at one year. Sixty one consecutive patients were enrolled and randomized into two groups: group A (n=32) treated with 30 mCi 131I; group B (n=29) treated with 30 mCi 131I plus an oral dose of lithium 900 mg/day, for 7 days. All patients were evaluated by whole body scan (WBS) with 123I and had serum TSH, thyroglobulin (Tg), and anti-Tg antibodies (TgAb) determined when they were hypothyroid on no thyroid hormone. Patients were reevaluated after one year with serum TSH, Tg, and TgAb determinations and WBS with 123I. The criteria for defining a successful outcome was a negative WBS and a serum Tg of <1. RESULTS Group A was composed of 28 women and four men (ages 25-71 years) with 2 having follicular thyroid carcinoma (FTC), 22 having papillary thyroid carcinoma (PTC) of 1-4.5 cm, and 8 having micro PTCs (mPTC) of 0.3-0.8 cm. Group B was composed of 26 women and 3 men (ages 20-63 years) with 3 having FTC, 15 having PTC of 1.2-3.5 cm, and 11 having mPTC of 0.2-0.8 cm. All patients had a history of a WBS after their post-therapeutic 131I dose that showed uptake in the cervical region. After one year, 22 patients from group A had a negative WBS (68.75%) and in group B, 27 patients had a negative WBS (93.1%). The successful rates for the follow-up WBS were significantly different (p=0.017). There were 19 patients in group A in whom the initial Tg was positive. Of these, 14 had a negative follow-up Tg (73.7%). Group B had 9 patients with a positive initial Tg and all of them had a negative follow-up Tg (100%). CONCLUSION The addition of lithium to treatment with 30 mCi 131I in thyroidectomized patients with low-risk DTC improved the efficacy of thyroid RA and therefore might be a better alternative than using higher doses of 131I for remnant ablation in these patients.

Basal serum thyroglobulin measured by a second-generation assay is equivalent to stimulated thyroglobulin in identifying metastases in patients with differentiated thyroid cancer with low or intermediate risk of recurrence.

Background: Guidelines for the follow-up of differentiated thyroid cancer (DTC) recommend the measurement of TSH-stimulated thyroglobulin (s-Tg) instead of basal Tg on T4 therapy (b-Tg). However, these guidelines were established using first-generation Tg assays with a functional sensitivity (FS) of 0.5-1.0 ng/ml. Current more sensitive second-generation Tg assays (Tg2G; FS 0.05-0.10 ng/ml) have shown that low-risk DTC patients with undetectable b-Tg rarely have recurrences. Objectives: This study was undertaken to compare b-Tg using a chemiluminescent Tg2G assay (Tg2GICMA; FS 0.1 ng/ml) with s-Tg in DTC patients with an intermediate risk of recurrence. Methods: We evaluated 168 DTC patients with a low (n = 101) and intermediate (n = 67) risk of recurrence treated by total thyroidectomy (147 also treated with radioiodine), with a mean follow-up of 5 years. Results: b-Tg was undetectable with the Tg2GICMA in 142 of 168 patients. s-Tg was <2 ng/ml in 138 of these 142 patients, and only 3 of these 138 (2%) presented metastases on cervical ultrasound (US). Of the 4 of 142 patients with s-Tg >2 ng/ml, 1 had cervical metastases seen after radioiodine. Furthermore, 26 of 168 patients presented detectable b-Tg with the Tg2GICMA; 17 of these 26 patients also presented s-Tg >2 ng/ml. In 10 of these 17 patients, metastases were detected. Cervical US or b-Tg were positive in 14 of 15 patients with recurrent disease. Globally, the sensitivity and negative predictive value of the Tg2GICMA plus US were 93 and 99%, respectively. Conclusion: b-Tg measured with a Tg2GICMA and cervical US, used together, are equivalent to s-Tg in identifying metastases in patients with DTC with a low or intermediate risk of recurrence.

Development, characterization and clinical validation of new sensitive immunofluorometric assay for the measurement of serum thyroglobulin

OBJECTIVE In the last decade, data published stressed the role of highly-sensitive thyroglobulin (Tg) assays in the follow-up of differentiated thyroid carcinoma (DTC) patients. The present study describes a new, highly-sensitive Tg assay, compares it with an available commercial assay, and validates it in the follow-up of DTC patients. SUBJECTS AND METHODS The immunofluorometric high-sensitivity Tg assay is based on monoclonal and polyclonal antibodies produced at our laboratories. It was validated in 100 samples of 87 patients with DTC submitted to total thyroidectomy, 87% of whom also received radioiodine. For correlation, all samples were also tested using a commercial Tg assay (Beckman Access) with functional sensitivity (FS) of 0.1 ng/mL. RESULTS The new method showed FS of 0.3 ng/mL. The correlation between the two methods was good (r = 0.74; p < 0.0001). The diagnostic sensitivity was 88.9%, and it was increased to 100% when combined with neck US. CONCLUSION This new, high-sensitivity Tg assay presented a good correlation with Beckman Access assay and with the clinical outcome of the patients. The continuous availability of a validated assay is an additional advantage for long term follow-up of DTC patients.

Avaliação de fatores clínicos, laboratoriais e ultrassonográficos preditores de malignidade em nódulos tiroidianos

OBJECTIVE: To evaluate the risk of malignancy in thyroid nodules through clinical, laboratory, ultrasonographic and cytological aspects. PATIENTS AND METHODS: 741 nodules of 407 patients. RESULTS: The cytology was benign (60,5%), indeterminate (23,3%), malignant (8,3%) or nondiagnostic (7,6%). The prevalence of cancer in indeterminate citology was 18,5% (16% in follicular lesions, 44% in suspicious). The diagnosis of malignancy was 17,2% (n = 70). The frequency of cancer in women (15,2%) was lower than in men (27,9%). There was an inverse relation between age and cancer risk. There was no statistical significance in the prevalence of cancer according to number, size of nodules or TSH levels. Hypoechogenicity and microcalcifications on ultrasound were risk factors. CONCLUSION: The risk of malignancy was higher in men, hypoechoic nodules, with microcalcifications and was inversely related to age. The TSH level was not an independent factor predictive of malignancy.

Seven-year follow-up of a juvenile female with papillary thyroid carcinoma with poor outcome, BRAF mutation and loss of expression of iodine-metabolizing genes

BACKGROUND Recent studies reported that BRAF V600E mutation, the most prevalent genetic event found in papillary thyroid carcinoma, is an independent poor prognostic marker. Additionally, it correlates with a less differentiated tumor stage due to reduced expression of key genes involved in iodine metabolism. We previously described a patient with BRAF V600E mutation in primary tumor and a new mutation (V600E+K601del) in the matched-lymph node metastases. In the present study we report an unusual clinical behavior of PTC and correlate with BRAF mutational status and level of expression of TSHR and NIS. METHODS Quantitative PCR (qPCR) was used to evaluate the NIS and TSHR level of expression in matched papillary thyroid carcinoma and adjacent normal tissue. RESULTS In this study, we presented a seven-year follow up of a juvenile papillary thyroid carcinoma patient who had an aggressive tumor harboring BRAF mutation, and failed to conventional therapy. We found a markedly decrease of NIS and TSHR expression in primary PTC compared to adjacent normal thyroid tissue. CONCLUSION Our findings suggest that BRAF mutational status and decreased NIS and TSHR expression in this patient may reduce radioiodine uptake and lead to a negative response to radioiodine therapy.