Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience.

BACKGROUND: Patients with thyroid microcarcinoma (TMC) have favorable long term prognoses. However, recurrences in the neck and distant metastases have been reported. The authors investigated independent factors associated with recurrence in an effort to define therapeutic guidelines. METHODS: Two hundred eighty-one patients (207 females, 74 males; mean age, 41.9 years) with a differentiated thyroid carcinoma < or = 1 cm in greatest dimension (mean size +/- standard deviation, 5.9+/-3.3 mm) were analyzed. The median follow-up time was 7.3 years. RESULTS: TMC diagnosis was incidental in 189 patients, and metastases were the first manifestation of the disease in the other 92 patients. Therapy included near-total thyroidectomy for 195 patients, lymph node dissection for 195, and therapeutic administration of radioiodine for 124. Eleven recurrences (3.9%) were observed 4.3+/-2.7 years (mean +/- standard deviation) after initial treatment: all had locoregional recurrence (4 in the thyroid bed and 7 in the lymph nodes), and in one of these the local recurrence was associated with lung metastases. Multivariate analysis showed that two parameters significantly influenced TMC recurrence, namely, the number of histologic foci (P < 0.002) and the extent of initial thyroid surgery (P < 0.01). Only 3.3% of patients with unifocal TMC treated with loboisthmusectomy had tumor recurrence. CONCLUSIONS: The recurrence rate for TMC appears to be low (3.9%). In the authors' view, loboisthmusectomy is the treatment of choice for patients with TMC when only one focus of cancer is found histologically, and total thyroidectomy is the optimal treatment for patients with multiple foci.

131I therapy for elevated thyroglobulin levels.

Assuming that the fractional uptake is the same, both after the administration of a diagnostic and a therapeutic activity, 131I uptake too low to be detected with 2-5 mCi may become detectable after the administration of 100 mCi. This should be performed routinely in patients with thyroglobulin levels above approximately 5 ng/mL during L-Thyroxine (LT4) treatment or 10 ng/mL off LT4 treatment for three main reasons: 1) in 80% of these patients, a post-therapy 131i total body scan showed foci of uptake in the neck or at distant sites, whereas in the other patients, metastases emerged clinically some years later; 2) 131I is not the only treatment modality, and, for instance, lymph node metastases may warrant further surgery; and 3) from a dosimetric point of view, the relevant parameter is the concentration of 131I, i.e., the ratio between the uptake and the mass of functioning tissue: a low uptake in a small metastasis may result in a higher 131I concentration than a higher uptake in a much larger metastasis.

Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence.

Germline point mutations in exons 10, 11, and 16 of the ret protooncogene have been identified as causative in multiple endocrine neoplasia type 2 and in familial medullary thyroid carcinoma (MTC). Somatic point mutations of the same gene, exclusively associated with codon 918 of exon 16, have also been reported in few cases of sporadic medullary thyroid carcinoma. We analyzed the blood and tumor DNA of 19 patients with sporadic MTC and 6 patients with primary parathyroid adenoma for point mutations at exons 10, 11, and 16 of the ret protooncogene by restriction analysis of the PCR-amplified product and by sequence analysis of exons 10 and 11. A Cys634-->Tyr mutation was found in both the tumoral and blood DNA of one patient, indicating that he was affected by an hereditary form of MTC, erroneously considered sporadic. In the other 18 patients with MTC, somatic point mutations of ret were found in 8 cases (44.4%). In 5 cases the mutation affected exon 16 (Met918-->Thr), and in 3 cases it affected exon 11 (Cys634-->Arg in 1 and Cys634-->Trp in 2); these 3 mutations were confirmed by sequence analysis. The remaining 10 patients had no mutation in exon 10 by either restriction analysis or sequence analysis. Clinical data showed that 75% of the patients whose tumor carried ret mutation had tumor recurrence and/or increased serum calcitonin concentrations during the postsurgical follow-up period as opposed to 10% of the patients without mutations (P < 0.02, by chi2 analysis). No ret mutation was found in the tumoral DNA from parathyroid adenomas. Our findings indicate that the somatic ret point mutation frequently found in sporadic MTC may affect not only exon 16 but also exon 11 and is associated with less favorable clinical outcome.

Early treatment of hereditary medullary thyroid carcinoma after attribution of multiple endocrine neoplasia type 2 gene carrier status by screening for ret gene mutations.

BACKGROUND: Germline missense point mutations of the ret proto-oncogene have been shown as causative in multiple endocrine neoplasia type 2 (MEN 2A and 2B) and in familial medullary thyroid carcinoma (FMTC). Most of the mutations are found in exon 10, 11, or 16 of the gene and are easily recognized by restriction analysis. METHODS: Using restriction analysis, we screened 58 subjects from nine kindreds. RESULTS: Family members (n = 16) already known to be affected with the disease carried the germline mutation. Among the 42 subjects apparently unaffected, 37 were not gene carriers and 5 were gene carriers. Basal and pentagastrin-stimulated serum calcitonin levels were normal in two patients and abnormal in three. All patients were treated with total thyroidectomy and central node dissection. In all cases multiple foci of MTC were shown at histologic examination. CONCLUSIONS: Our data indicate that genetic screening of MEN2 pedigrees allows the early identification of gene carriers. Because surgery of MTC in the preclinical phase has high probability of curing these patients, we suggest genetic screening soon after birth and total thyroidectomy in gene carriers as early as possible.

Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine.

From 1969 to 1990 there were 309 patients with differentiated thyroid carcinoma (241 papillary and 68 follicular) treated with radioactive iodine for functioning node metastases alone (n = 191) or distant metastases (n = 118) with or without node metastases. These patients represented 32.7% of 945 patients treated in our institution during the same period. Initial treatment included near-total thyroidectomy and 131I ablation of postsurgical thyroid residue, followed by L-thyroxine suppressive therapy. At the end of follow-up (mean 5.8 years), 146 patients (76.4%) in the group with nodal metastases were considered cured, as assessed by clinical and laboratory evaluation including whole body scan (WBS) and serum thyroglobulin (Tg) levels; 32 patients (16.7%) had persistent disease. Loss of 131I uptake in persistent metastatic lesions occurred in five patients (2.6%), and newly developed distant metastases occurred in eight patients (4.2%). Of the patients with distant metastases, 36.4% were cured by 131I. Distant metastases from papillary carcinomas had a higher cure rate than follicular carcinomas (p < 0.01). The metastases of four patients (5.2%) lost the property to take up radioiodine. Lung and bone metastases detectable by WBS but not by radiography were most likely to be cured by 131I. The overall survival at the end of follow-up was 95.8% in patients with only lymph node metastases and 76.0% in those with distant metastases. Tumor-related deaths were 3.6% and 23.7%, respectively. Our data indicate that 131I therapy is highly effective in the treatment of lymph node metastases from differentiated thyroid carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaplastic thyroid-carcinoma - a retrospective clinical and immunohistochemical study.

We reviewed 34 patients with histologically proven anaplastic thyroid carcinoma, representing 3.1% of all thyroid carcinomas treated from 1970 to 1992 in our Institution. Mean age at diagnosis was 63.1+/-10.3 years. Initial treatment consisted of near total thyroidectomy in 14 patients, partial thyroidectomy in 6 and no more than a biopsy in 14. After surgery 11 patients received external radiotherapy associated with chemotherapy (R+C), 8 patients had only chemotherapy (C), and 11 patients had only radiotherapy (R). Two patients, both in the group treated with R+C, are still alive, with a survival from the diagnosis of 23 and 26 months, respectively. Mean survival of the group treated with R+C (16.1+/-8.2 months) was significantly higher than that of patients treated only with C (6.2+/-4.4 months; p<0.01) or only with R (5.1+/-2.6 months; p<0.0004). In the group treated with R+C, patients submitted to near total or partial thyroidectomy had a mean survival of 15.0+/-8.8 months, similar to that of patients who had only a biopsy (17.2+/-7.9 months), suggesting that the outcome was affected by post-surgical therapy rather than by surgery per se. Twenty-two tumors were also assayed by immunohistochemistry for p53 and PCNA expression. p53 was expressed in 16/22 (72.2%) cases, with no correlation with sex, age, presence of differentiated component or survival. Comparing tumors with <30% or >30% p53 positive cells a tendency to longer (but not significant) survival was found in tumors with lower p53 expression. PCNA was expressed in all cases, with a percentage of positive cells ranging from 15% to 90%, and was not correlated with sex, age, differentiation, or survival. A positive correlation was found between PCNA and p53 expression (r=0.58; p=0.0039). In conclusion, our data indicate that in anaplastic thyroid carcinoma the use of combined R+C has some advantages with respect to single therapy. As in other aggressive malignancies; p53 and PCNA expression is increased irrespective of the response to therapy or the outcome.

Detection of thyroid-stimulating antibody using Chinese hamster ovary cells transfected with cloned human thyrotropin receptor.

A clone of Chinese hamster ovary (CHO) cells transfected with the cloned human TSH receptor (CHO-R) was used to optimize an assay for thyroid-stimulating antibody (TSAb), measuring adenylate cyclase stimulation by purified immunoglobulin G from patients with Graves' disease. Optimal sensitivity to bovine TSH (1 mU/L) and TSAb was obtained using hypotonic buffer and measuring extracellular cAMP. In time-response experiments, TSAb stimulation was maximal after 2 h of incubation in hypotonic buffer. Under these conditions, a significant stimulation by Graves' immunoglobulin G was obtained with 33 of 35 (94%) samples from patients with untreated Graves' disease and with 21 of 23 (91%) from patients who relapsed after a course of antithyroid drugs. On the other hand, TSAb was detected in only 12 of 20 (60%) patients who were euthyroid during methimazole treatment and in 4 of 11 (36%) who were euthyroid after a course of antithyroid drugs. All samples from Graves' patients were also tested for TSAb activity on FRTL-5 cells. The results of cAMP stimulation in FRTL-5 and CHO-R showed a fairly good correlation (r = 0.60; P < 0.0001). In particular, of the 58 patients with active Graves' disease (35 with untreated hyperthyroidism and 23 relapsed after methimazole), 43 (74%) were positive in both assays, 3 (5%) were negative in both, 11 (19%) were negative in FRTL-5 and positive in CHO-R, and 1 (1.7%) was negative in CHO-R and positive in FRTL-5. In conclusion, CHO cells transfected with the cloned human TSH receptor are suitable for the clinical assay of TSAb. The sensitivity of this assay is higher than that obtained using FRTL-5 cells, having the additional advantages of expressing the human TSH receptor and requiring less cumbersome procedures for cell culture.

Thyroid hypoechogenic pattern at ultrasonography as a tool for predicting recurrence of hyperthyroidism after medical treatment in patients with Graves' disease.

An abnormal thyroid echographic pattern characterized by a diffuse low echogenicity has been described in Hashimoto's thyroiditis and Graves' disease. The aim of the present work was to study the relationship between thyroid hypoechogenicity and the outcome of treatment for hyperthyroidism with antithyroid drugs in patients with Graves' disease. The study group included 105 patients who underwent a course of methimazole treatment. Thyroid ultrasonography was carried out at diagnosis, and autoantibodies to thyrotropin receptor (TR-ab) were measured at the end of treatment. During the follow-up after methimazole treatment, 87/105 (83%) patients had relapse of hyperthyroidism and 18/105 (17%) were in remission. Recurrence of hyperthyroidism occurred in 71/76 (93%) patients with thyroid hypoechogenicity and in 16/29 (55%) of those with normal thyroid echogenicity (chi 2 = 19.0; p less than 0.0001). Positive TR-ab values at the end of methimazole treatment were found in 59/76 (78%) patients with thyroid hypoechogenicity and in 12/29 (41%) patients with normal thyroid echogenicity (chi 2 = 10.9; p less than 0.0001). Sixty-five/87 (74%) patients with relapse of hyperthyroidism and 6/18 (33%) of those who remained euthyroid were TR-ab-positive at the end of methimazole treatment (chi 2 = 9.8; p less than 0.002). The finding of thyroid hypoechogenicity at diagnosis had higher specificity (0.81) and sensitivity (0.72) with respect to TR-ab positivity at the end of methimazole treatment (0.74 and 0.66 respectively) for the prediction of relapse of hyperthyroidism. Therefore, the evaluation of thyroid echographic pattern can be considered a useful prognostic tool in patients with Graves' disease.