PURPOSE: To evaluate the diagnostic accuracy of routine calcitonin measurement in patients with nodular thyroid disease. METHODS: Consecutive patients with nodular thyroid disease (n = 640) were studied. Serum calcitonin levels were measured under basal conditions, and when basal values were between 10–100 pg/mL, testing was repeated after pentagastrin (PG) stimulation. Patients with previously diagnosed or familial medullary thyroid cancer (MTC) were excluded. Patients were operated on when basal or stimulated calcitonin >100 pg/mL or when other surgical indications were present. RESULTS: Four cases of MTC were identified. MTC was diagnosed in 75% of patients with basal calcitonin >100 pg/mL. One out of 11 patients with basal calcitonin between 10–100 pg/mL was diagnosed with MTC. PG stimulation resulted in elevation in 4 cases, where 1 case was diagnosed with MTC. Positive predictive value for basal calcitonin levels in the preoperative diagnosis of MTC was 5% for values between 10–100 pg/mL and 100% for values >100 pg/mL. Possible reasons for false positivity were papillary thyroid cancer in 17%, renal insufficiency in 8.3%, Hashimoto thyroiditis in 17% and β-blocker use in 33%. Positive predictive value for the PG test (>100 pg/mL) was 25% in the entire series. The cost of adding calcitonin measurement (±PG stimulation) to the preoperative work-up, resulted in €912.68 per MTC patient to detect the disease. CONCLUSION: Basal calcitonin measurement together with PG stimulation in cases of basal calcitonin >10 pg/mL detects MTC in 0.62% of patients with nodular thyroid disease.
Calcitonin* ; Diagnosis ; Hashimoto Disease ; Humans ; Pentagastrin ; Renal Insufficiency ; Thyroid Diseases* ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroid Nodule

BACKGROUND: Serum calcitonin is a sensitive and specific marker for diagnosis of medullary thyroid carcinoma (MTC) and its determination leads to accurate preoperative diagnosis and gives chances of definite cure. However, since many non-MTC diseases are also associated with calcitonin elevation, its significance in patients with mild or moderately elevated basal serum calcitonin levels is not clear. Furthermore, the normal value of calcitonin using immunoradiometric assay (IRMA) kit has not so far been definitely ascertained. This study is aimed at assessing the clinical significance of routine measurement of serum basal calcitonin concentration in nodular thyroid disease patients and evaluating the pentagastrin stimulation test in case of mild or moderate elevation of basal calcitonin level. We also measured serum calcitonin value in 408 normal individuals. METHODS: The basal serum calcitonin concentrations using a commercial IRMA kit (Medgenix CT-U.S.-IRMA) were measured in 818 patients with nodular thyroid disease (average age 45 years with a range from 13 to 82 years; 125 males and 693 females) who visited thyroid clinics in Samsung Medical Center between June 1997 and December 1998. Serum concentrations of T3, T4, TSH and thyroid autoantibodies were measured and ultrasonography of thyroid and thyroid scan using 131I or 99mTc-pertechnetate were performed in all patients. We also studied 408 healthy subjects without any thyroid disease (average age 48 years with a range from 20 to 86 years; 224 females). RESULTS: The calcitonin value in normal subjects was found to range from 0 to 13 pg/mL, and it was shown that men had higher calcitonin level than women (p< 0.05). The rate of serum calcitonin elevation (> 10pg/mL) in nodular thyroid disease was 1.71% (14/818), and the incidence of MTC was 0.73% (6/818) in this study. MTC was found in all patients with basal serum calcitonin levels more than 100 pg/mL. Pentagastrin stimulation test was also required to diagnose MTC in patients with basal serum calcitonin levels between 30 and 100pg/mL. The calcitonin concentration stimulated by pentagastrin increased more than 400pg/mL or more than 3.8 times of basal concentration. It was possible to diagnose MTC with fine needle aspiration and cytology in only one case out of six patients with MTC. CONCLUSION: Fine needle aspiration and cytology in diagnosing MTC was not sensitive and not devoid of false positive results. We confirmed that serum calcitonin measurement was very useful means for the preoperative diagnosis of unsuspected MTC. Pentagastrin stimulation test may be a reliable means of evaluation in nodular thyroid disease patients with mild or moderate elevation of basal calcitonin level. We recommend routine measurement of serum calcitonin concentration in patients with nodular thyroid disease.
Autoantibodies ; Biopsy, Fine-Needle ; Calcitonin* ; Diagnosis ; Female ; Humans ; Immunoradiometric Assay ; Incidence ; Male ; Pentagastrin ; Reference Values ; Thyroid Diseases* ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroid Nodule ; Ultrasonography

Multiple endocrine neoplasia (MEN) Ila is an inherited disease characterized by the development of medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. It has been shown to be associated with germ-line mutatians in the RET proto-oncogene. Presymptomatic screening of medullary thyroid carcinoma in MEN IIa families enables the early diagnosis of this tumor with its significant morbidity, We describe a 19-year-old woman fmm a MEN IIa family who was founded by DNA analysis to be a gene carrier of MEN IIa and then was diagnosed, using a pentagastrin stimulation test, as having presymptomatie medullary thyroid carcinoma She underwent thyroidectomy and histologic examination confirmed medullary thyroid carcinoma. It is cancluded that direct genetic analysis for mutations in the RET proto-oncogene should be the diagnstlc test of choice for identifying family members at risk for MEN IIa and thyroidectomy on the basis of genetic analysis is a rational course of action.
DNA ; Early Diagnosis ; Female ; Genes, vif ; Humans ; Hyperparathyroidism ; Male ; Mass Screening* ; Multiple Endocrine Neoplasia ; Multiple Endocrine Neoplasia Type 2a* ; Pentagastrin ; Pheochromocytoma ; Proto-Oncogenes ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy ; Young Adult

BACKGROUND: Conventional biochemical screening for family members with hereditary medullary thyroid cancer (MTC) is associated with problems of sensitivity and, specificity and it frequently detects gene carriers only after disease progression. Molecular genetic screening tests that detect germ-line point mutations of the RET proto-oncogene has changed our approach to hereditary MTC. In this study we screened members of a large Korean family that had a history of hereditary MTC by a molecular genetic method and propose a therapeutic approach in managing the disorder. METHODS: Using DNA acquired from peripheral blood leukocytes of the index patient, we performed PCR and direct sequencing of exon 10 of the RET proto-oncogene. PCR-RFLP using an Mbo II restriction enzyme was performed on family members who were at risk of MTC according to the family pedigree. Basal serum calcitonin level was determined in family members who had a point mutation of the RET proto-oncogene and a pentagastrin stimulation test was performed in 3 members. RESULTS: Genetic analysis in the index case revealed a mutation in exon 10, codon 618 of the RET proto-oncogene (TGC to AGC). Out of 28 members who were at risk of MTC, 24 members participated in the screening test. 9 members tested positive for a mutation in the same chromosomal location as the index patient by PCR-RFLP. Basal serum calcitonins were above 100 pg/mL in 2 members. 3 members who had a RET point muatation but a normal basal serum calcitonin level participated in the pentagastrin stimulation test and the results were negative in all members. We found a small medullary thyroid carcinoma that had a diameter of 0.2 cm in a 16 years old boy according to a negative pentagastrin stimulation test and who had received a prophylactic total thyroidectomy. He had no evidence of a lymph node metastasis. CONCLUSION: We detected a germ-line mutation of the RET proto-oncogene in codon 618 of Exon 10 by a molecular genetic method in a family with a hereditary MTC and found 9 members that had a negative history of MTC but had a RET point mutation. There was a very small MTC found in a 16 years old boy who had a normal pentagastrin stimulation test result. Therefore, It is recommended that a prophylactic total thyroidectomy be performed as well as in members that have a mutation of the RET proto-oncogene because MTC can metastasize early in its disease course.'
Adolescent ; Calcitonin ; Codon ; Disease Progression ; DNA ; Exons ; Germ Cells* ; Germ-Line Mutation ; Humans ; Leukocytes ; Lymph Nodes ; Male ; Mass Screening* ; Molecular Biology ; Neoplasm Metastasis ; Pedigree ; Pentagastrin ; Point Mutation* ; Polymerase Chain Reaction ; Proto-Oncogenes* ; Sensitivity and Specificity ; Thyroid Gland* ; Thyroid Neoplasms* ; Thyroidectomy