Paule Gardet

Long-term results and prognostic factors in patients with differentiated thyroid carcinoma

A multivariate analysis of the prognostic factors was carried out on a series of 546 differentiated thyroid cancers followed for 8 to 40 years. For survival, the highest risk factor was associated with age; tumors diagnosed in patients younger than 45 years had higher relapse‐free survival (RFS) and total survival (TS) rates and a slower growth rate. In children, although the RFS and TS at 15 years were high, they decreased later. The second independent prognostic factor was histology. There was no difference between papillary and follicular well‐differentiated (FWD) tumors, but follicular moderately differentiated (FMD) had lower TS and RFS. Among FMD cancers, relapses occurred earlier and the interval between relapse and death was shorter. The third factor was sex. Tumors tended to disseminate more in male than in female patients. The survival rate after relapse was the same, however, suggesting that the growth rates are not different. The presence of palpable lymph nodes also had a significant independent impact on both TS and RFS. Patients treated after 1960 have a better outcome than patients treated earlier, although they did not differ in age distribution, histologic characteristics, sex ratio, or incidence of palpable lymph nodes. The distribution of time intervals between treatment and relapse was not compatible with an exponential failure time model but fit with a log‐logistic model. Relapses can occur as late as 30 years or more after initial treatment. Elevated levels of circulating thyroglobulin have been observed in about 12% of the patients who had been in complete remission for longer than 20 years.

Chemotherapy in metastatic nonanaplastic thyroid cancer: experience at the Institut Gustave-Roussy.

Forty-nine patients with metastatic nonanaplastic thyroid carcinoma were treated over a 10-year period. Five successive chemotherapeutic protocols were used: a combination of doxorubicin, etoposide, 5-fluorouracil and cyclophosphamide; elliptinium acetate; doxorubicin; cispiatin; and the combination of doxorubicin and cispiatin. Results obtained with the different protocols were very disappointing, with only two objective responses (3%). Phase II trials with new chemotherapeutic agents are warranted in selected cases of nonanaplastic metastatic thyroid carcinoma.

Construction and clinical validation of a sensitive and specific assay for serum mature calcitonin using monoclonal anti-peptide antibodies.

Using calcitonin (CT) as an hapten, we have generated a library of monoclonal antibodies. Six monoclonal antibodies were developed and analyzed with respect to affinity and specificity for epitopes on CT by enzyme linked immunosorbent assay and radioimmunoassay. These antibodies were used in the construction and the optimization of a two-site monoclonal immunoradiometric assay (m-IRMA) for CT. We used a combination of two monoclonal antibodies to develop an assay which is rapid (overnight incubation), sensitive (10 pg/ml) and strictly specific for the mature form of calcitonin, ie the 32 amino acid-long polypeptide bearing a prolineamide as the C-terminal residue. This assay was utilized to demonstrate that mature calcitonin circulates as heterogeneous molecular species resulting from polymerization of calcitonin by disulphide linkage and/or by aggregation on irrelevant proteins. The clinical relevance of this assay was studied on a series of patients with medullary carcinoma of the thyroid (MCT) and the characteristics of the assay was compared with those of a conventional polyclonal radioimmunoassay. The m-IRMA for CT proved to be useful for both the diagnosis and the follow-up of MCT.

A new immunoradiometric assay (IRMA) system for thyroglobulin measurement in the follow-up of thyroid cancer patients

A new commercially available kit for thyroglobulin (Tg) measurement [immunoradiometric assay (IRMA) system based on monoclonal antibodies] was used in 479 patients with thyroid carcinoma. The effective working range was 1 ng/ml, and results were strongly correlated with our homemade radioimmunoassay (RIA). This IRMA method is less susceptible to interferences of auto-antibodies than our RIA. During thyroxine (T4) treatment, the Tg level was undetectable in 98% of patients after total thyroid ablation, in 91% after total thyroidectomy and in 42% after lobectomy only. In this situation, Tg was found in all patients with large metastases and in 88% of those with small metastases. Following T4 withdrawal, Tg was detectable in all patients with neoplastic disease and in 13% of those in complete remission after total thyroid ablation. In conclusion, Tg measured with this IRMA method appears to be a reliable marker of differentiated thyroid carcinoma.

Screening for Multiple Endocrine Neoplasia Type 2A with DNA-Polymorphism Analysis

Multiple endocrine neoplasia type 2a has been shown to be genetically linked to a locus near the centromere of chromosome 10. The availability of polymorphic DNA probes for the region permits the use of restriction-fragment-length polymorphisms (RFLP) to identify carriers of the gene for this cancer syndrome. As part of a French national program, DNA probes were used in a genetic-linkage study of 130 members of 11 families of European and North African origin. In these families there was no recombination between the mutation causing multiple endocrine neoplasia type 2a and two of the three probes used. All 11 families were informative for at least one of the three markers, and linkage information was adequate to provide genetic counseling to 8 families. We found that RFLP analysis is much more useful in predicting the carrier state than conventional endocrine challenge, especially in younger people, but accuracy is maximal when both methods are employed. We conclude that genetic screening allows the identification of those who are at risk for multiple endocrine neoplasia type 2a at any age with a high level of certainty. After initial screening with DNA, tests for early neoplastic change may be directed toward those determined to be at high risk.

Value of venous catheterization and calcitonin studies in the treatment and management of clinically inapparent medullary thyroid carcinoma

Seventeen patients with medullary thyroid carcinoma (MTC) underwent venous catheterization (VC) for sampling and serum calcitonin (CT) assay. The VC was performed either after an initial treatment in order to detect cervical recurrences and metastases (16 patients) or to prove abnormal CT thyroid secretion before any treatment (one patient). In 16 of the 32 tumoral localizations suspected by VC(50%), a tumoral focus was proven. For selective/peripheral CT gradient value superior to 2.50, 12 localizations of 12 (100%) were proven and for CT gradient value between 1.50 and 2.50, four localizations of 15 (26.6%) were proven. In six patients with exclusive cervical MTC secreting sites, treatment induced a total remission in two cases (12%) and improved in four cases (23%). The authors conclude that VC has a real value to localize MTC secreting sites. A total remission or an improvement can be obtained after treatment when VC detects exclusive cervical tumors.

Radioiodinated meta-iodobenzylguanidine uptake in medullary thyroid cancer: a french cooperative study

Fifty meta‐iodobenzylguanidine (MIBG) scintiscans were performed in three groups of medullary thyroid cancer (MTC) patients. Group 1 (n = 11) included treated patients with normal calcitonin levels; Group 2 (n = 24) included patients with elevated calcitonin levels due to sporadic and isolated MTC; Group 3 (n = 15) included patients with elevated calcitonin levels due to familial MTC or multiple endocrine neoplasia Type IIA syndrome (MEN). In Group 1 three pheochromocytoma were depicted by MIBG scintiscan. In Group 2 MTC was seen in a small number of patients (3 of 24). In Group 3, besides adrenal hyperplasia and pheochromocytoma four patients, MIBG scintigraphy showed where MTC had localized and spread in almost half of patients (7 of 15). MIBG uptake occurred in patients with relatively high calcitonin level (>0.6 nmol/l). These data indicate that in patients with familial MTC or MEN syndrome, MIBG scintiscan can be useful not only in detecting associated pheochromocytoma, but also in showing MTC.

Follow-up of patients with differentiated thyroid carcinoma. Experience at Institut Gustave-Roussy, Villejuif

The recent introduction of sTSH assays allows for a definite control of the inhibition of TSH secretion. Clinical examination and serum thyroid hormone measurements are necessary to obviate hyperthyroidism. Relapses may occur after decades of apparent complete remission. Follow-up should be pursued throughout the patients lifetime. Two specific means allow the detection of relapses at a stage when X-rays are still normal: measurement of serum thyroglobulin and 131I total body scan. Their combined use is recommended.

Detection of a germline mutation at codon 918 of the RET proto-oncogene in French MEN 2B families

Multiple endocrine neoplasia type 2A (MEN2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) are three dominantly inherited disorders linked to the same disease locus on chromosome 10. Two types of germline mutation of the RET proto-oncogene, which codes for a transmembrane tyrosine kinase, are associated with MEN 2. Missense mutations at cysteine residues in the extra-cytoplasmic domain are exclusively associated with MEN 2A and FMTC. In MEN 2B patients, a single point mutation at codon 918 has recently been characterized, leading to the replacement of a methionine by a threonine within the RET tyrosine kinase domain. We now report the identification of a mutation at codon 918 in the germline of 16 patients out of 18 unrelated MEN 2B families analyzed. In these families we have been able to demonstrate that, in five cases, the mutation arose de novo, and that, in one kindred, it was coinherited with the disease. These results indicate that a unique mutation at codon 918 of the RET gene is the most prevalent genetic defect causing MEN 2B, but also that rare MEN 2B cases are associated with different mutations yet to be defined.

Linkage analysis of hereditary thyroid carcinoma with and without pheochromocytoma

SummaryThe use of polymorphic DNA segments as markers for the gene for the multiple endocrine neoplasia (MEN) syndrome, type 2a, allows the identification of family members at high risk for developing medullary carcinoma of the thyroid and other tumors, especially pheochromocytoma. Several families have also been identified in which medullary thyroid carcinoma is inherited, but pheochromocytoma is not seen. We have analysed 18 families, 9 with MEN 2A and 9 with medullary carcinoma of the thyroid without pheochromocytoma, with probes specific for the pericentromeric region of chromosome 10 and conclude that the mutations for the two presentations are closely situated. Genetic heterogeneity of the susceptibility locus was not seen among this sample of 18 families. The genetic mutation for medullary carcinoma was in disequilibrium with the marker alleles of the two closely linked probes. IRBPH4 and MCK2. These data suggest that different mutant alleles of the same gene or closely linked mutations account for the variation in penetrance of pheochromocytoma in families with hereditary, medullary thyroid carcinoma.