The ERCC2 protein is an evolutionary conserved ATP-dependent helicase that is associated with a TFIIH transcription factor complex and plays an important role in nucleotide excision repair. Mutations in this gene are responsible for xeroderma pigmentosum and also for Cocayne syndrome and trichothiodystrophy. Several single nucleotide polymorphisms have been identified in the ERCC2 locus. Among them, a G23591A polymorphism in the codon 312 results in an Asp → Asn substitution in a conserved region and a A35931C polymorphism in the codon 751 results in a Lys → Gln substitution. Because these polymorphisms have been associated with an increased risk for several types of cancers, we carried out an hospital based case-control study in a Caucasian Portuguese population to evaluate the potential role of these polymorphisms on the individual susceptibility to thyroid cancer. The results obtained did not reveal a significant association between each individual polymorphism studied (G23591A and A35931C) and an increased thyroid cancer risk, but individuals homozygous for non-wild-type variants are overrepresented in patients group. The evaluation of the different haplotypes generated by these polymorphisms showed that individuals simultaneously homozygous for rare variants of both polymorphisms have an increased risk for thyroid cancer [adjusted odds ratio (OR) 3.084; 95% confidence interval (95% CI), 1.347-7.061; P = 0.008] and for papillary thyroid–type tumors (adjusted OR, 2.997; 95% CI, 1.235-7.272; P = 0.015) but not for follicular thyroid–type tumors. These results suggest that genetic polymorphisms in this gene might be associated with individual susceptibility towards thyroid cancer, mainly papillary-type tumors, but larger studies are required to confirm these results.

OBJECTIVE:To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer. DESIGN AND METHODS:A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries. RESULTS:There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a <2% recurrence rate after surgery alone, and that post-surgical radioiodine confers recurrence and cause-specific survival benefits in patients, strongly suspected of having persistent disease or known to have tumor in the neck or distant sites. In other patients, there is limited evidence that after complete thyroidectomy and adequate lymph node dissection performed by an expert surgeon, post-surgical radioiodine provides clear benefit. When there is any uncertainty about the completeness of surgery, evidence suggests that radioiodine can reduce recurrences and possibly mortality. CONCLUSION:This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age <16 years, or with unfavorable histology.

Purpose: A 68-year-old man with metastatic follicular thyroid carcinoma had T3 hyperthyroidism. Material and Methods: A bone scan showed intense uptake in the thyroid and multiple areas of increased uptake in the skeleton. Hyperthyroidism persisted after total thyroidectomy. Treatment with I-131 induced a transient state of euthyroidism lasting approximately 9 months. Further tumor growth and relapse of hyperthyroidism eventually occurred and the patient died 25 months after surgery. Molecular and cytogenetic analyses were performed. Results: No mutations were detected of either of the thyrotropin receptor or of the &agr; subunit of the stimulatory guanine-nucleotide-binding proteins. Hyperthyroidism was unlikely the result of thyroid-stimulating receptor antibodies. Comparative genomic hybridization analysis showed that the tumor was characterized by multiple chromosomal imbalances. Conclusions: This is an unusual case of follicular thyroid carcinoma with initial high I-131 uptake by the thyroid and bone metastases and concurrent hyperthyroidism. Despite the increased I-131 uptake in the tumor, I-131 treatment only transiently controlled the hyperthyroidism and had no effect on tumor size. The cause of hyperthyroidism remained unknown. T3 predominance was unlikely the result of type 2 deiodinase overexpression because loss of genetic material was demonstrated at chromosome 14 long arm, where type 2 deiodinase is mapped.

ThyroidVol. 15, No. 12 Images in ThyroidologyChoroidal Metastasis from Sporadic Medullary Thyroid CarcinomaF. Rosário, A. Garrão, J. Laranjeira, M.J. Bugalho, E. Limbert, and L.G. SobrinhoF. RosárioSearch for more papers by this author, A. GarrãoSearch for more papers by this author, J. LaranjeiraSearch for more papers by this author, M.J. BugalhoSearch for more papers by this author, E. LimbertSearch for more papers by this author, and L.G. SobrinhoSearch for more papers by this authorPublished Online:11 Jan 2006https://doi.org/10.1089/thy.2005.15.1401AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Choroidal Metastasis from Sporadic Medullary Thyroid Carcinoma." , 15(12), pp. 1401–1402FiguresReferencesRelatedDetailsCited byChoroidal metastasis as initial presentation of aggressive medullary thyroid carcinoma with widespread mediastinal, brain, pituitary, bone, lung, and liver metastasis: Case report and literature reviewInternational Journal of Surgery Case Reports, Vol. 61Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine-needle aspiration. A case report and review of the literature16 April 2018 | Diagnostic Cytopathology, Vol. 46, No. 9Choroidal and Orbital Metastases from Thyroid Cancer Nikola Besic and Zala Luznik29 April 2013 | Thyroid, Vol. 23, No. 5Metastatic Medullary Carcinoma of Thyroid Presenting as a Dural-Based Mass: Case Report and Review of Literature25 January 2013 | Endocrine Pathology, Vol. 24, No. 1Optic Disc and Choroidal Metastasis from Sporadic Medullary Thyroid Carcinoma: Case Report and Review of the LiteratureOnkologie, Vol. 34, No. 11Simultaneous Eyelid and Choroidal Metastases 36 Years After Diagnosis of Medullary Thyroid CarcinomaOphthalmic Plastic & Reconstructive Surgery, Vol. 24, No. 1Red Lesions of the Iris, Choroid, and Skin Secondary to Metastatic Carcinoma of the Thyroid: A ReviewSurvey of Ophthalmology, Vol. 52, No. 5 Volume 15Issue 12Dec 2005 InformationCopyright 2005, Mary Ann Liebert, Inc.To cite this article:F. Rosário, A. Garrão, J. Laranjeira, M.J. Bugalho, E. Limbert, and L.G. Sobrinho.Choroidal Metastasis from Sporadic Medullary Thyroid Carcinoma.Thyroid.Dec 2005.1401-1402.http://doi.org/10.1089/thy.2005.15.1401Published in Volume: 15 Issue 12: January 11, 2006PDF download

As differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We have proposed, in a previous issue of this Journal, an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies. We report here the case of a paradigmatic patient with papillary thyroid carcinoma, with the goal of illustrating the benefits of applying this algorithm in routine clinical practice. We also offer expanded and additional comments on various issues in the management of DTC.

Since exposure to ionizing radiation, a risk factor for thyroid cancer, may produce genotoxins potentially eliminated by glutathione-S-transferases, we conducted a case control study to evaluate the role of the GSTM1- and GSTT1-null genotypes and GSTP1 polymorphisms in thyroid cancer. The frequency of GSTP1 Ile/Ile, GSTM1-, and GSTT1-null genotypes was increased in cancer patients when compared with control population. Considering the genotypes over-represented in thyroid cancer patients as potential risk genotypes, we carried out an odds ratio (OR) analysis considering the presence of none, one, two, or three risk genotypes. The results obtained showed that the presence of three potentially risk alleles (GSTM1 null, GSTT1 null, and GSTP1 Ile/Ile) lead to a significant OR increase for all the cases, irrespective of the type of tumor (OR=2.91), for papillary (OR=3.64) but not for follicular tumors. The presence of GSTP1 Ile/Ile leads to a significant later age of tumor onset when compared with GSTP1 Ile/Val and Val/Val (P<0.05), suggesting a possible association between GSTP1 Ile/Ile and the age of disease manifestation. These results suggest that combined GST polymorphisms lead to a moderate increased risk for thyroid cancer, especially for the papillary type, and GSTP1 polymorphisms might modulate the age of onset of the disease.

OBJECTIVE:Because differentiated (follicular and papillary) thyroid cancer (DTC) may recur years after initial treatment, the follow-up of patients with DTC is long term. However, this population has changed, with more individuals being discovered at an earlier stage of the disease, so that previous follow-up protocols based mostly on data from high-risk patients no longer apply. We sought to develop an improved protocol for the follow-up of low-risk patients with DTC based on the findings of recent studies.METHODS:We analysed recent literature on the follow-up of DTC.RESULTS:Recent large studies have produced three important findings: (i) in patients with low-risk DTC with no evidence of disease up to the 6- to 12-month follow-up, diagnostic whole-body scan adds no information when serum thyroglobulin (Tg) is undetectable and interference from anti-Tg antibodies is absent; (ii) use of recombinant human thyroid-stimulating hormone to aid Tg measurement is effective and provides greater safety, quality-of-life and work productivity than does levothyroxine withdrawal with its attendant hypothyroidism; and (iii) ultrasonography performed by an experienced operator is the most sensitive means of detecting neck recurrences of DTC.CONCLUSIONS:We present a revised follow-up protocol for low-risk patients taking into account the above findings. This protocol should help clinicians enter a new era of monitoring characterized by greater safety, simplicity, convenience and cost savings.

Our study attempted to assess the possible induction and persistence of an adaptive response in lymphocytes of thyroidectomized thyroid cancer patients treated with 131I (2,590 MBq, corresponding to whole body doses in the range of 200–300 mGy), to a testing dose of mitomycin C (MMC) in vitro. The cytogenetic endpoint studied was the induction of micronuclei in cytokinesis‐blocked peripheral blood lymphocytes, immediately before treatment and 1, 6 and 24 months after therapy. One month after therapy, induction of micronucleated cytokinesis‐blocked lymphocytes (‰) by MMC was lower (34.6 ± 7.7) than before therapy (52.1 ± 5.0). In 7 of 11 patients this reduction was significant. However, at 6 months, induction of micronuclei was markedly higher (133.1 ± 13.6). This significant increase was observed regardless of the decrease at 1 month. At 24 months, the frequency of micronucleated cells decreased (84.8 ± 5.5), but remained higher than before treatment. The results obtained 1 month after therapy could reflect adaptation due to radiation, or a higher rate of early apoptosis or cell death, with bone marrow suppression, visible as a lower response in vitro towards MMC. At 6 months, recovery of the lymphocyte population may occur, and higher responses to MMC in vitro could reflect higher chromosomal instability in the previously irradiated stem cells with a concomitant disappearance of adaptation, whereas at 24 months the results show a tendency to return to pretherapy values. © 2002 Wiley‐Liss, Inc.

OBJECTIVE Recent studies have assigned clinical significance and prognostic value to the detection of thyroglobulin (Tg) mRNA in the blood of patients subjected to total thyroidectomy for a papillary or follicular thyroid carcinoma. In this study, we investigated the diagnostic specificity of Tg mRNA detection, analysing blood samples from healthy volunteers and from patients previously subjected to total thyroidectomy for reasons other than a carcinoma of the follicular epithelium. DESIGN AND METHODS Total RNA was extracted from whole blood, reverse-transcribed and the cDNA amplified for Tg and glyceraldehyde-3-phosphate dehydrogenase with specific primers. Expression levels were analysed by using a semi-quantitative PCR. In a few cases, Lymphoprep gradients were used to separate the mononuclear and polymorphonuclear cells prior to further analysis by reverse transcription/PCR. RESULTS Our data suggested that all individuals expressed Tg mRNA. Moreover, no differences in the expression levels between subjects with and without thyroid glands were documented. Documentation of Tg expression by the mononuclear and polymorphonuclear layers in patients without thyroid glands support the hypothesis that both lymphocytes and granulocytes express Tg and may justify a background expression in blood, independently of the presence of follicular cells in circulation. CONCLUSIONS Tg mRNA expression is not limited to follicular cells of the thyroid gland, and its expression by normal blood cells should be considered in tests performed for diagnostic purposes.

In this article we describe detailed pathological and molecular genetics studies in a consanguineous kindred with Pendred's syndrome. The index patient was a 53-year-old female patient with congenital deafness and goiter. Her parents were first-degree cousins. She had a large goiter (150 g) that had been present since childhood. One of her sisters and a niece are also deaf and have goiter as well. The presence of Pendred's syndrome was confirmed by a positive perchlorate test and the demonstration of a Mondini malformation. Thyroid function tests (under levothyroxine [LT4] therapy) were in the euthyroid range with a thyrotropin [TSH] level of 2.8 microU/mL (0.2-3.2), a serum total thyroxine (T4) of 90 nmol/L (54-142), and a serum total triiodothyronine (T3) of 2.7 nmol/L (0.8-2.4). Total thyroidectomy was performed, and the mass in the right lobe was found to have invaded adjacent tissues. The histopathological findings were consistent with a follicular carcinoma with areas of anaplastic transformation and lung metastasis. The patient was treated twice with 100 mCi 131iodine (3,700 MBq) and received suppressive doses of LT4. Postoperatively, the serum thyroglobulin (Tg) levels remained markedly elevated (2,352 to 41,336 ng/mL). The patient died of a sudden severe episode of hemoptysis. Sequence analysis of the PDS gene performed with DNA from the two relatives with Pendred's syndrome revealed the presence of a deletion of thymidine 279 in exon 3, a point mutation that results in a frameshift and a premature stop codon at codon 96 in the pendrin molecule. We concluded that prolonged TSH stimulation because of iodine deficiency or dyshormonogenesis in combination with mutations of oncogenes and/or tumor suppressor genes, may result in the development of follicular thyroid carcinomas that undergo transformation into anaplastic cancers. It is likely that these pathogenetic mechanisms have been involved in the development of aggressive metastatic thyroid cancer in this unusual patient with Pendred's syndrome.

The relationship between the presence of high frequencies of chromosomal aberrations in peripheral lymphocytes and predisposition to cancer has been suggested for some cancer diseases. In nonfamilial thyroid cancer, the few reports available are equivocal. The aim of this study was to assess the possible chromosomal instability in peripheral blood lymphocytes from 22 patients suffering from nonfamilial thyroid cancer. For this purpose, 2 classic cytogenetic assays, the chromosomal aberrations assay and cytokinesis-blocked micronucleus assay, were chosen. The frequency of chromosomal aberrations excluding gaps (%) was 1.68 +/- 1.39 (mean value +/- SD) for the patients group versus 2.20 +/- 1.87 for the control group. The frequency of binucleated lymphocytes with micronuclei ( per thousand) was 5.41 +/- 3.51 (mean value +/- SD) for the patients group versus 5.37 +/- 3.21 for the control group. The results obtained revealed no significant differences between both groups. The present study reinforces the idea that constitutional chromosomal instability in peripheral blood lymphocytes is not visible in nonfamilial thyroid carcinomas.

This study aimed to assess two end-points of DNA damage, namely chromosomal aberrations and micronuclei in peripheral lymphocytes, and their possible relationship with oxidative stress (which may be related to DNA damage and repair) in thyroid cancer patients receiving therapeutic doses of (131)I. Nineteen patients receiving 2590 MBq (70 mCi) were studied. Chromosomal aberrations were scored using standard cytogenetic methods and micronuclei scored in cytokinesis-blocked lymphocytes. Oxidative stress was assessed by determining thiobarbituric acid-reactive substances in blood, total plasma antioxidant status and serum uric acid levels. All parameters were assessed before treatment and 1 and 6 months after (131)I administration. The frequency of micronucleated cells per 1000 binucleated cells scored (mean +/- SEM) increased significantly from 5.21 +/- 0.80 to 9.68 +/- 1.22 1 month after treatment (P < 0.01) and to 8.42 +/- 1.28 6 months after treatment (P < 0.05). The frequency of cells with chromosomal aberrations, excluding gaps, per 100 cells, increased significantly from 1.68 +/- 0.41 to 3.47 +/- 0. 55 1 month after treatment (P < 0.01) and to 4.05 +/- 0.46 6 months after treatment (P < 0.01). Oxidative stress parameters showed slight modifications over the time period studied, but the differences were not significant except for a decrease in thiobarbituric acid-reactive products 6 months after therapy (P < 0. 05) and in serum uric acid concentration 1 and 6 months after therapy (P < 0.01). This report demonstrates slight but significant and persistent DNA damage in (131)I-treated patients as assessed by cytogenetic assays. There was no clear correlation between the cytogenetic findings and oxidative stress parameters studied.

The case report is presented of a 47-year-old white woman with Cushing's disease treated by bilateral adrenalectomy in June 1981. A first computed tomography (CT) scan in September 1984 showed a voluminous pituitary adenoma with invasion of the sphenoid sinus and left parasellar extension. The tumour increased progressively in size, a suprasellar extension developed and the optic chiasm was eventually affected. In March 1988 and June 1989 the patient underwent two surgeries for the pituitary tumour, the second followed by radiotherapy. During this period, the ACTH values varied between 100 pmol/l and 403 pmol/l (normal: < 13 pmol/l). After radiotherapy, a progressive shrinking of the tumour was observed and the ACTH concentrations decreased to a lowest value of 27.5 pmol/l. The patient was clinically well until September 1993 when, suddenly, the plasma ACTH concentration increased to very high levels (greater than 965 pmol/l). There was no evidence of tumour growth on the sellar CT scan. In January 1995, an ACTH-producing pituitary carcinoma was diagnosed, based on the presence of bone metastases. The patient died in May 1995.

Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG-->ACG) causing a Met-->Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T-->C transversion was identified causing a Cys-->Arg substitution. In conclusion, absence of a germline mutation in RET exons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630.