Familial non-medullary thyroid carcinoma (FNMTC): analysis of fPTC/PRN, NMTC1, MNG1 and TCO susceptibility loci and identification of somatic BRAF and RAS mutations

Linkage analysis has identified four familial non-medullary thyroid carcinoma (FNMTC) susceptibility loci: fPTC/PRN (1p13.2-1q22), NMTC1 (2q21), MNG1 (14q32) and TCO (19p13.2). To date, there is no evidence for the involvement of genes from the RAS/RAF signalling pathway in FNMTC. The aim of our study was to evaluate the role of the four susceptibility loci, and RAS/RAF signalling pathway genes, in FNMTC. In total, 8 FNMTC families, and 27 thyroid lesions from family members (22 papillary thyroid carcinomas (PTCs): 11 classic, 10 of the follicular variant and 1 of the mixed variant; 4 follicular thyroid adenomas (FTAs) and 1 nodular goitre (NG)), were evaluated for the involvement of the four susceptibility regions, using linkage and loss of heterozygosity (LOH) analyses. BRAF and H-, N- and K-RAS mutations were also screened in the 27 lesions and patients. Linkage analysis in seven informative families showed no evidence for the involvement of any of the four candidate regions, supporting a genetic heterogeneity for FNMTC. Twenty tumours (74%), of which 18 were PTCs, showed no LOH at the four susceptibility loci. The remaining seven tumours (four PTCs, two FTAs and one NG) showed variable patterns of LOH. Fourteen tumours (52%) had somatic mutations: BRAF-V600E mutation was observed in 9 out of the 22 PTCs (41%); and H-RAS and N-RAS mutations were detected in 5 out of the 22 PTCs (23%). Our data suggest that the four candidate regions are not frequently involved in FNMTC and that the somatic activation of BRAF and RAS plays a role in FNMTC tumourigenesis.     

Epidemiology of thyroid microcarcinoma found in autopsy series conducted in areas of different iodine intake.

The prevalence of thyroid microcarcinomas found at autopsies is 100-1000 times higher than in clinical cancer. The epidemiological and histological characteristics of thyroid microcarcinomas in consecutive series of autopsies performed in two areas of different iodine intake were investigated. Iodine deficient (ID) area: n = 222 (M = 109, F = 113), median age: 74-76 years, median iodine excretion (MIE) of nursing home residents from this area: 70 microg/g creatinine. Iodine sufficient (IS) area: n = 221 (M = 132, F = 89), median age: 68 years, MIE: 500 microg/g creatinine. When compared to the IS area, the results obtained in the ID area showed a higher thyroid weight (mean 27.75 g +/- 18.43 g vs. 16.5 g +/- 9.6 g, p < 0.0001) and a larger number of goitrous glands (50/222 vs. 5/221, p < 0.0001). Altogether 21 microcarcinomas were found (4.74%) with no iodine intake- or gender-related difference: ID n = 11 (4.95%), M/F = 8/3; IS n = 10 (4.52%), M/F = 6/4. Microcarcinomas seemed to be more prevalent in the 40-59-year age group. All microcarcinomas were of the papillary type. In conclusion, compared to clinical cancer, thyroid microcarcinomas are characterized by a two-scale higher prevalence, are not related to iodine intake, gender or nodularity, are most exclusively of the papillary type.     

A Greek family with a follicular variant of familial papillary thyroid carcinoma: TCO, MNG1, fPTC/PRN, and NMTC1 excluded as susceptibility loci.

The familial form of nonmedullary thyroid carcinoma (FNMTC) has been recognized as a distinct clinical entity and is characterized by multifocality and a more severe phenotype than its sporadic counterpart. The majority of FNMTC pedigrees are small in size, show variable modes of inheritance, and may present with a variety of additional benign thyroid disorders. The existence of marked phenotypic differences between FNMTC families suggests that there is genetic heterogeneity. Recent studies have mapped a susceptibility locus for FNMTC at 2q21. This locus appears particular relevant to families with at least one case of the follicular variant of papillary thyroid cancer (fvPTC). We describe the clinical and pathologic characteristics of a large three-generation fPTC kindred, with two of the four PTC patients presented with the follicular variant of PTC. It is of interest the occurrence of PTC in three siblings within a period of 3 years. In addition, multinodular goiter (MNG) was diagnosed in seven individuals, lymphocytic thyroiditis in four, while one diagnosed with a benign adenoma. From the PTC patients, one had MNG and fvPTC, one MNG, lymphocytic thyroiditis and papillary pattern of PTC, one lymphocytic thyroiditis and fvPTC, and one MNG and papillary pattern of PTC. The inheritance pattern was autosomal dominant with incomplete penetrance and women were affected more frequently than men. Considering all PTC-affected individuals, the limit of detection (LOD) score we got for this family on 2q21 was 0.5. The low LOD score is caused by a PTC patient who does not share the affected haplotype, suggesting that maybe a new locus for PTC predisposition is present in this kindred. Linkage analysis also excluded TCO, MNG, and fPTC/PRN as susceptibility loci to FNMTC in this family.     

The T1799A BRAF mutation is not a germline mutation in familial nonmedullary thyroid cancer

OBJECTIVE: Familial nonmedullary thyroid cancer (FNMTC) is relatively common but its predisposing genetic alteration is unclear. As the somatic T1799A BRAF mutation is highly prevalent in papillary thyroid cancer, the aim was to test whether this mutation was a susceptibility mutation for FNMTC. SUBJECTS AND METHODS: The T1799A BRAF mutation as a possible germline mutation was examined in 40 subjects from 23 families with a history of FNMTC. Direct DNA sequencing was performed on white blood cell DNA samples to analyse the mutation status. RESULTS: No T1799A BRAF mutation was found in this group of subjects as germline mutation. CONCLUSION: The T1799A BRAF mutation is not a germline mutation or susceptibility genetic event for FNMTC.     

A new form of familial multi-nodular goitre with progression to differentiated thyroid cancer

We report a kindred with euthyroid multi-nodular goitre (MNG) of adolescent onset. Two of the seven subjects with MNG have progressed to papillary thyroid cancer. One affected male had nodular kidney disease, and breast cancer occurred in one affected female. Genes that were candidates on the basis of the associated kidney (PAX8) and breast diseases (sodium iodide symporter (NIS)), were sequenced. No mutations were found in the coding region, intron/exon splice sites or in the promoter sequences (from -1248 relative to the translation initiation codon) of PAX8. Similar results were obtained for NIS. Subsequently, microsatellite analyses were performed on 14 informative family members. We used 2 to 3 markers per locus for 6 loci (on chromosomes 1,2,3,14,19,X) previously reported to predispose to MNG and/or familial non-medullary thyroid cancer (FNMTC). On the basis of non-significant logarithm of the odds ratio (LOD) scores or inheritance of different alleles in affected individuals, all loci have been excluded. Thyroidectomy specimens from three members of the kindred show multiple benign lesions, with papillary cancer in two. The morphological features do not resemble those seen in familial adenomatous polyposis, Cowden syndrome, or in multiple oxyphil lesions. From these findings and from the absence of any linkage to any of the known loci associated with MNG or FNMTC, we suggest that this represents a new form of inherited MNG with a significant risk of progression to papillary carcinoma.     

Prognostic factors of differentiated thyroid cancers. 536 cases

Five hundred thirty-six patients with papillary (n = 327) or follicular (n = 209) carcinoma of the thyroid treated between 1957 and 1985 in the same endocrine department are presented. Treatment was either an unilateral extracapsular lobectomy with isthmectomy, for isolated nodules only (n = 253), or a total thyroidectomy - with or without radio-iodine administration - or, exceptionally, a partial thyroidectomy. The impact of histologic type, age and sex of the patients, type of presentation and limited surgery (i.e. unilateral lobectomy in nodular carcinoma) were tested for prognostic value (total or relapse-free survival). The main factors are: initial tumour extension (almost no survival after 10 years in case of metastasis; 87.98 +/- 0.04% 20 years estimate of percent surviving in exclusive thyroid localization); histologic type (relative death rate: predominant papillary: 0.28, follicular well differentiated: 0.88, moderately differentiated: 2.54 (p less than 0.01); age (prognosis as better as the patient is younger); sex (worse prognosis for men above 40 years). Unilateral lobectomy is an unhazardous treatment with a survival rate 92.41 +/- 0.03% at 20 years for follicular and papillary nodular carcinoma.     

Familial non-medullary thyroid carcinoma displays the features of clinical anticipation suggestive of a distinct biological entity

Non-medullary thyroid carcinoma (NMTC) is mostly sporadic, but familial clustering is described. We aimed to compare the features of patients with sporadic and familial NMTC (FNMTC) patients and to assess whether FNMTC patients with parent-child relationship exhibit the 'anticipation' phenomenon (earlier age at disease onset and increased severity in successive generations). Among 300 NMTCs followed in the Section of Endocrinology (University of Siena, Italy), 34 (11.3%) patients, all with the papillary histotype, (16 kindred), met the criteria of FNMTC. Twenty-seven of them (79.4%) exhibited a parent-child relationship and seven (20.6%) a sibling relationship. These patients were compared with 235 patients with sporadic papillary thyroid cancer (PTCs). To analyze the features of FNMTC of the first and second generations, we cumulated the series of Siena with 32 additional FNMTC patients (15 kindred) from the Department of Endocrinology-Endocrine Oncology, Thessaloniki, Greece. Significant difference between sporadic PTC and FNMTC patients included more frequent tumor multifocality (P=0.001) and worse final outcome in FNMTC patients (P=0.001). Among 47 FNMTC with parent-child relationship, we found an earlier age at disease presentation (P<0.0001), diagnosis (P<0.0001), and disease onset (P=0.04) in the second generation when compared with the first generation. Patients in the second generation were more frequently males (P=0.02); their tumors were more frequently multifocal (P=0.003) and bilateral (P=0.01), had higher rate of lymph node metastases at surgery (P=0.02) and worse outcome (P=0.04) when compared with the first generation. In conclusion, FNMTC displays the features of clinical 'anticipation' with the second generation acquiring the disease at an earlier age and having more advanced disease at presentation.     

Chromosomal aberrations by comparative genomic hybridization in thyroid tumors in patients with familial nonmedullary thyroid cancer.

PURPOSE: Nonmedullary thyroid cancer is the most common form of thyroid cancer and its familial form (FNMTC) is increasingly recognized as a distinct clinical entity. However, the genetic background of FNMTC is still poorly understood and the causative gene(s) have not yet been identified. METHODS: Because comparative genomic hybridization allows for screening of the entire tumor genome simultaneously for chromosomal gains and/or losses without prior knowledge of potential aberrations, we used this technique in thyroid normal and neoplastic samples from FNMTC patients (1) to analyze whether chromosomal aberrations would correlate with inheritance pattern, and/or clinicopathologic features and (2) to compare comparative genomic hybridization (CGH) findings in familial tumors with those already known in sporadic differentiated thyroid cancers. RESULTS: No common germline or somatic chromosomal aberrations were observed in patients with FNMTC because the frequencies and most locations of chromosomal aberrations in familial tumors were also common in sporadic tumors. However, some somatic aberrations were only found in familial tumors (gains in 2q, 3q, 18p, and 19p). Common aberrations in familial tumors corresponded to several locations of candidate genes already reported for sporadic thyroid tumorigenesis. CONCLUSIONS: Our findings suggest that chromosomal aberrations in thyroid tumors in patients with FNMTC are not related to inheritance pattern but rather to tumorigenesis.     

Long‐term follow‐up of patients with bone metastases from differentiated thyroid carcinoma – surgery or conventional therapy?

OBJECTIVE: Surgery of bone metastases from differentiated thyroid carcinoma seems indicated in individual patients. This study was performed (1) to analyse retrospectively patients with bone metastases from differentiated thyroid carcinoma and (2) to evaluate the impact of surgery of bone metastases on survival. PATIENTS AND DESIGN: We analysed 41 consecutive patients with bone metastases from differentiated thyroid carcinoma who had undergone thyroid surgery at Vienna University Hospital since 1966. The median follow-up time was 12 years. There were 24 females and 17 males with a mean age of 60 +/- 12 years. Primary tumour histology was follicular in 35 and papillary in six patients. Radioiodine treatment was performed in 32 with a mean administered activity of 27 +/- 24 GBq 131I. Metastases restricted to the skeleton were found in 22 whereas in 19 individuals additional extraskeletal distant metastases were seen. Twenty-seven patients had multiple bone metastases. In 21 individuals, up to five bone metastases were surgically removed with the intention of cure. RESULTS: Univariate analysis identified total thyroidectomy (P = 0.003), lymph node surgery (P = 0.001), radioiodine therapy (P = 0.036), and the absence of extraskeletal distant metastases (P = 0.017) as significant predictors of survival. Multivariate analysis failed to identify significant prognostic factors. In the subgroup of patients with distant metastases limited to the bones, univariate analysis identified, in addition to thyroid and lymph node surgery, the surgical extirpation of the bone metastases as a significant prognostic factor associated with improved survival (P = 0.025). CONCLUSIONS: These findings indicate that in patients without additional extraskeletal distant metastases, the radical surgical extirpation of bone metastases from differentiated thyroid carcinoma might be associated with improved survival.     

Prevalence and prognosis of familial follicular thyroid carcinoma

Although the responsible gene has not yet been identified, patients with differentiated thyroid carcinoma, including papillary and follicular carcinomas, demonstrating a family history have been reported and patients having one or more family members with differentiated carcinoma among their first-degree relatives are designated as having familial nonmedullary thyroid carcinoma (FNMTC). In this study, we investigated the biological characteristics, including prognosis, of familial follicular carcinoma. Three hundred and nineteen patients who underwent initial surgery for follicular thyroid carcinoma between 1987 and 2004 who were enrolled in this study. Of these 319 patients, 6 patients (1.9%) in 6 families were classified as having familial follicular carcinoma based on the criteria described above. The incidence of aggressive characteristics such as male gender, age 45 years or older, poor differentiation, widely invasive carcinoma, tumor larger than 4 cm and distant metastasis at diagnosis did not differ between familial and sporadic follicular carcinomas. One patient with familial follicular carcinoma underwent re-operation because of newly detected papillary carcinoma in the remnant thyroid 160 months after the initial surgery, but none of the 6 patients with familial carcinoma showed recurrence or died of follicular carcinoma. We can therefore conclude that FMNTC of the follicular type is very rare and there is no evidence that familial follicular carcinoma is more aggressive or has a worse prognosis than sporadic follicular carcinoma. The therapeutic strategy for follicular carcinoma might depend on conventional prognostic factors such as poor differentiation and distant metastasis at diagnosis, but not on whether the carcinoma is familial or sporadic.     

Frequent, aggressive behaviors of thyroid microcarcinomas in korean patients

The incidence of thyroid microcarcinoma is rising due to the frequent use and improvement of fine-needle aspiration biopsy and ultrasonography. Since the recent update of the TNM (Tumor, Node, Metastasis) staging system for thyroid cancer, the importance of lymph node metastasis became more prominent. In the present study, we evaluated the prognostic factors and extension of thyroid microcarcinomas in Korean patients. The clinical and pathological findings in patients with thyroid microcarcinomas in a Korean hospital from January through December 2004 were evaluated. A total of 302 (50.2%) out of 601 cases of thyroid cancers were microcarcinomas. Evaluation of the histology revealed that nearly all of the cases (300 of 302) were of the papillary type. Analyzing patients of papillary thyroid microcarcinomas, 273 (91.0%) out of 300 patients of papillary microcarcinomas were women. Seventy-eight (26.0%) cases contained multiple tumor masses (> or =2), including 49 (16.3%) cases that were bilateral. There were 84 (28.0%) cases of extrathyroidal extensions and 89 cases (29.7%) of lymph node metastasis, but no cases of distant metastases. Application of the new staging system revealed 7 (2.3%) cases that changed from stage III to stage IVA. Thyroid microcarcinomas were also associated with poor prognostic factors and appear to exist at relatively higher cancer stages. Therefore, it is important to treat them as early and as vigorously as possible with extensive surgery, radioactive iodine therapy, and thyroxine suppression.     

Presence of BRAF V600E in very early stages of papillary thyroid carcinoma.

OBJECTIVE: Extremely small (often 0.5-4 mm) incidental thyroid malignancies (incidental microcarcinomas, IM) might be discovered at histological examination after surgery in patients who were operated on for benign thyroid conditions. Morphologically, these malignancies have virtually always features of differentiated papillary thyroid carcinoma (PTC). Although IM are in general considered of little clinical significance their potential malignant behavior cannot be ignored. BRAF(V600E) mutation has emerged as the most prevalent genetic alteration in PTC. DESIGN: The incidence of BRAF(V600E) was studied in 85 microdissected cases of IM detected in two series of 334 and 398 patients operated on for benign thyroid disease in 2005 and in 2006, respectively. IM ranged in size from 0.5 to 4 mm and all featured cytology consistent with the diagnosis of PTC. Microdissected lesions were also evaluated for galectin-3 expression by immunohistochemistry. MAIN OUTCOME: BRAF(V600E) was identified in 15 out of 85 (17.6%) IM compared to 45% clinically evident PTCs (n = 91) and 38.3% preoperatively identified microcarcinomas (n = 47). CONCLUSION: These data suggest that it is possible to find BRAF(V600E) in IM despite their extremely small (<1 mm) size. This is not a formal demonstration that IM can evolve into clinical PTC, but on these bases, patients with BRAF(V600E) IM may need to be managed more carefully.     

Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour

The role of angiogenesis and lymphangiogenesis in thyroid cancer pathogenesis has not been elucidated. Patterns for tumour behaviour and metastasic spread vary according to tumour type and whether differences in the angiogenic or lymphangiogenic phenotype influence the route for tumour metastases or determine a more aggressive behaviour has not been fully explored. The angiogenic and lymphangiogenic phenotypes of a large cohort of thyroid proliferative lesions (n=191) were studied. Using immunohistochemistry for CD34, lymphatic vessel endothelial receptor-1 (LYVE-1) (specific markers for vascular and lymphatic endothelium respectively), vascular endothelial growth factor (VEGF-A), VEGF-C and fibroblast growth factor-2 (FGF-2), this study analyses microvascular density (MVD), lymphatic vascular density (LVD), and expression of angiogenic and lymphangiogenic factors in normal thyroid (NT; n=19), multinodular goitre (n=25), toxic multinodular goitre (n=8), Graves' hyperplasia (n=22), follicular adenoma (n=54), papillary carcinoma (PC; n=27), incidental papillary microcarcinoma (PMC; n=8), follicular carcinoma (FC; n=20) and medullary carcinoma (MC; n=8). MVD was decreased in proliferative lesions, benign and malignant, compared with NT (P<0.0001). In contrast, VEGF-A expression was increased in thyroid carcinomas (PC, FC and MC) when compared with PMC, benign lesions and NT (P<0.0001). LVD was higher in PC and PMC (P=0.001), and VEGF-C expression was increased in PC (P<0.0001). Despite higher LVD and increased expression of VEGF-A and VEGF-C in thyroid cancers, these markers were not related to poor prognosis in terms of tumour size, multifocality and/or presence of lymphatic or distant metastases. In conclusion, angiogenesis is reduced in thyroid proliferative lesions compared with NT tissue. However, VEGF-A expression is upregulated in thyroid cancers. Lymphangiogenesis and VEGF-C expression are increased in thyroid tumours prone to lymphatic metastases. This may be an important mechanism underlying the differences in metastatic behaviour between papillary and follicular thyroid cancer.     

The highly malignant phenotype of anaplastic thyroid carcinoma cell lines is recessive

OBJECTIVE: The aim of our studies was to determine whether the phenotype of the anaplastic thyroid carcinomas is dominant or recessive. In fact, it is hypothesized, on the basis of epidemiological and pathological data, that undifferentiated thyroid carcinomas are derived from differentiated tumours through a mechanism of tumour progression. DESIGN: Cell hybrids have been generated by cell fusion of anaplastic thyroid carcinoma cell lines, which show a highly malignant phenotype, to cell lines deriving from differentiated thyroid carcinoma, which show a non-tumorigenic or a poorly tumorigenic phenotype. All of the parental cell lines showed impaired p53 gene function. RESULTS: The cell hybrids contained alleles from the parental cell lines. All of the cell hybrids showed a lower growth rate compared with the parental undifferentiated carcinoma cell lines and were unable to grow in soft agar and to induce tumours after injection into athymic mice. CONCLUSION: Taken together, these findings suggest that the highly malignant phenotype of the anaplastic thyroid carcinoma is achieved by the impairment of gene functions that negatively regulate cell growth, rather than by the activation of dominant oncogenes.     

Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplification

Overexpression of cyclin D1 occurs in several malignancies, often due to gene amplification, and this has been associated with aggressive tumor behavior, a higher incidence of lymph node metastases, and a poorer prognosis. The role of cyclin D1 in the pathogenesis of thyroid malignancy is unknown; however, cyclin D1 expression has been reported to occur in a proportion of well differentiated thyroid carcinomas. Micropapillary carcinomas of the thyroid are common incidental findings that almost always behave in an indolent manner and remain quiescent. However, rare microcarcinomas behave aggressively and metastasize early, giving rise to clinically significant disease. We hypothesized that cyclin D1 might play a role in the aggressive behavior of metastasizing papillary microcarcinomas. We reviewed the histopathology reports of 2,000 patients who underwent thyroid surgery at our institution between 1995-1999 and identified 22 patients who presented with gross regional metastases from a primary papillary microcarcinoma. These patients formed the index cohort for this analysis. As controls, we selected 34 patients with nonmetastasizing microcarcinomas. We studied these tumors for immunoreactivity to cyclin D1 on immunohistochemistry and analyzed 13 tumors that diffusely expressed cyclin D1 for gene amplification by differential PCR. Twenty of the 22 (90.9%) metastasizing papillary microcarcinomas expressed cyclin D1, compared with 3 of the 34 (8.8%) nonmetastasizing papillary microcarcinomas (P < 0.001). However, of the 13 tumors that showed diffuse immunoreactivity for cyclin D1 on immunohistochemistry, none showed amplification of the cyclin D1 gene on differential PCR. We conclude that cyclin D1 is significantly overexpressed in metastasizing papillary microcarcinomas of the thyroid. This is likely due to mechanisms other than gene amplification. Cyclin D1 immunohistochemistry may be a valuable tool in predicting metastatic potential in papillary microcarcinomas.     

Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome

Papillary thyroid carcinoma usually is sporadic, but may occur in a familial form. The complete clinical and pathological phenotype of familial papillary thyroid carcinoma (fPTC) has not been determined, and the susceptibility gene(s) is unknown. We investigated the clinical and pathological characteristics of an unusually large three-generation fPTC kindred to characterize more fully the clinical phenotype. We performed linkage analysis to determine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed the otherwise rare entity of papillary renal neoplasia (PRN) in two kindred members, one affected with PTC and the other an obligate carrier. The multifocality of PRN in one subject adds weight to the likelihood of a true genetic predisposition to PRN. Both genetic linkage and sequence analysis excluded MET, the protooncogene of isolated familial PRN, as the cause of the fPTC/PRN phenotype. A genome-wide screening and an investigation of specific candidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed for markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia. The predisposing gene in a large kindred with this syndrome has been mapped to 1q21.     

On the prevalence of familial nonmedullary thyroid cancer in multiply affected kindreds.

Clinical and genetic studies of familial nonmedullary thyroid cancer (FNMTC) have yielded conflicting results concerning the aggressiveness of the tumors, and uncertainty of their genetic makeup. In most reports of multiply affected families, the composition of the kindreds has favored families of 2 affected members. Using data for differentiated thyroid cancer (DTC) provided by the Surveillance Epidemiology and End Results (SEER) branch of the National Cancer Institute, and fine-needle aspiration data from Mayo Clinic, I found that the likelihood of 2 cases of sporadic DTC (RR) in a 9-member first-degree family was 1.25% of all DTC families, amounting to 39.4% of 306 multi-hit families reported in the literature. To study the remaining affected families I used the Bernouilli trials model of exact probability. The 60.6% of non-RR, multiply affected families are mostly concentrated in kindreds of 2 to 5 affected members. In 2-hit families, 62%-69% of affected members are sporadic (RR) cases. In families having 3 or more affected members, fewer than 6% have 1 or more sporadic (R) cases, and fewer than 0.15% have 2 or more. In families of 3 to 5 affected members, more than 96% of affected members have the familial (F) trait. Approximately 1 of 338 DTC cases carries the F-trait. Since approximately 40% of multiply affected member first-degree kindreds of DTC, and a significant majority of 2-hit families, are composed of clinically evident, sporadic cases only clinical and genetic investigations of FNMTC should center on families of 3 or more affected members.     

Localization and expression of thyroid hormone receptors normal and neoplastic human thyroid

The aim of this study was to investigate the regional expression of thyroid hormone nuclear receptor forms (TR(alpha) and TR(beta)) and isoform (TR(alpha1) and TR(beta2)) mRNAs in normal and neoplastic (benignant and malignant) human thyroid tissue. Tumor specimens from patients with thyroid carcinomas (papillary: 5 cases; follicular: 5 cases; anaplastic: 2 cases), thyroid follicular adenomas (7 cases) and tissue from normal thyroid glands (12 cases) were analyzed by in situ hybridization and semiquantitative RT-PCR for the expression of TR(alpha1) and beta, as well as for the isoform alpha2 that does not bind the hormone. In normal tissues, TR(alpha2) was expressed at lower levels compared to TR(alpha1) (alpha1/alpha2 = 4.3). In papillary and follicular carcinomas, the expression of TR(alpha1) and TR(beta) did not change as compared with normal thyroid tissue and adenomas (0.87 +/- 0.15 SD vs 0.89 +/- 0.17 densitometric units, DU, and 0.15 +/- 0.02 vs 0.14 +/- 0.03 DU, respectively). However, the expression of TR(alpha2) was significantly higher in differentiated carcinomas compared to normal thyroid tissue and adenomas (0.47 +/- 0.05 vs 0.20 +/- 0.05 DU, p < 0.05) with alpha1/alpha2 = 1.4. In anaplastic carcinoma all TRs were absent. We concluded that both normal and pathological thyroid tissues, with the exception of anaplastic carcinoma, express all TRs in thyreocites and that differentiated thyroid carcinomas are associated in enhancing the expression of TR(alpha2) mRNA.     

Is [18F]-2-fluoro-2-deoxy-d-glucose (FDG) scintigraphy with non-dedicated positron emission tomography useful in the diagnostic management of suspected metastatic thyroid carcinoma in patients with no detectable radioiodine uptake?

OBJECTIVE: Dedifferentiation of thyroid cancer leads to an inability of thyroid cells to concentrate iodine. In these cases, imaging methods that allow an accurate detection of recurrence and/or metastases at an early stage are essential for an adequate management of patients. Positron emission tomography using [18F]-2-fluoro-2-deoxy-d-glucose and a dedicated (dPET-FDG) or non-dedicated (nPET-FDG) camera has been suggested as a potential tool for the detection of tumour foci. DESIGN AND METHODS: This prospective study was undertaken to evaluate nPET-FDG in 51 consecutive patients (18 men, 33 women) with differentiated thyroid cancer (33 papillary, 11 follicular, four insular and three oncocytic (Hurthle-cell) thyroid carcinomas). Selection criteria were high thyroglobulin (Tg) levels (>10 ng/ml off-levothyroxine treatment) and no detectable radioiodine uptake, on a whole body scan performed with a high dose, in the absence of iodine contamination. RESULTS: Results were interpreted in terms of assumed presence of tumoral tIssue. Sensitivity of nPET-FDG was similar to that of conventional imaging modalities (67%). False negative nPET-FDG (n=16) were observed mostly in cases of micro-lesions (lymph nodes or lung metastases). Conversely, nPET-FDG identified new tumoral sites in 11 cases. Better sensitivity was found for nPET-FDG in patients with Tg levels higher than 15 microg/l (P<0.05). On a patient basis, results of nPET-FDG were equivalent to that of dPET-FDG. Finally, nPET-FDG changed treatment strategy in seven patients. CONCLUSIONS: nPET-FDG has a high sensitivity for the detection of tumour sites in patients when pathological iodine uptake cannot be demonstrated and appears to be a useful method in patients with elevated Tg levels, especially when dedicated PET is either unavailable or impractical.