Basal Calcitonin Levels Research Articles

Prognostic Variables and Calcitonin in Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a nonepithelial, neuroendocrine tumor with a more aggressive clinical behavior than differentiated thyroid cancer. The purpose of the study was to review a single institution's experience with MCT since 1969. Retrospective cohort study. A retrospective review of 30 patients treated for MTC at a tertiary care referral center between 1969 and 2000. There were 17 female and 13 male patients, median age at presentation was 38 years, and median follow-up for survivors was 12.4 years. Seventy percent of patients had sporadic MTC, 6.7% had familial MTC, 16.7% had multiple endocrine neoplasia syndrome type IIA, and 6.7% had multiple endocrine neoplasia syndrome type IIB. The cumulative overall survival rates at 5, 10, and 20 years were 97%, 88%, and 84%, respectively; disease-free survival rates were 97%, 74%, and 29%, respectively. Advanced tumor stage (P = .014) and multiple endocrine neoplasia syndrome type IIB predicted decreased disease-specific survival. Variables affecting disease-free survival were post-thyroidectomy calcitonin level (P = .001), vascular invasion (P = .005), perineural invasion (P = .010), extrathyroidal extension (P < .001), and the presence of nodal metastases (P = .001). Locoregional control rates were 83% at 5 years and 70% at 10 years. Vascular invasion (P = .004), extrathyroidal extension (P = .008), and post-thyroidectomy basal calcitonin level (P = .003) predicted locoregional failure. Many patients in the series experienced prolonged survival despite elevated calcitonin levels. Long-term disease-free survival is uncommon in MTC, but the study data indicate that the majority of patients with MTC live for prolonged periods, despite biochemical evidence of persistent disease. Adverse pathological features such as extrathyroidal extension and vascular and perineural invasion were predictors of disease recurrence. The use of serum markers in the follow-up of patients with MTC must be interpreted within the clinical context.

Surgical Management of Thyroid Carcinoma

Thyroid carcinoma has a unique biologic behavior characterized by early spread to regional lymph nodes and occasional extrathyroidal soft tissue extension but a low incidence of distant metastasis and infrequent disease-related death. Therefore, controversy exists over the proper extent of thyroidectomy and regional lymph node dissection in patients with differentiated thyroid carcinoma (DTC) and medullary thyroid carcinoma (MTC). The modest disease-specific mortality makes it unlikely that the extent of surgery will ever be the subject of a prospective randomized trial. Although more extensive cervical surgery may have only a limited effect on the duration of survival in patients with DTC, it may significantly improve quality of life by minimizing cervical recurrence. The high rates of cervical recurrence in patients with DTC and MTC have alerted physicians to the importance of fine-needle aspiration biopsy and ultrasonography for the diagnosis, preoperative staging, and follow-up of thyroid cancer. In patients with MTC, death caused by disease is uncommon in the absence of radiographically evident distant metastasis at the time of thyroidectomy. Cervical recurrence is even more common with MTC, and the need for compartment-oriented lymphadenectomy is accepted as standard surgical treatment to minimize disease recurrence. Postoperatively, calcitonin (CT) levels can be used to guide clinical management, but basal CT levels should not be used to direct the timing of prophylactic thyroidectomy in affected high-risk patients with familial MTC.

Elevated Basal Calcitonin Levels in a Patient with a Hürthle-Cell Carcinoma of the Thyroid and Neuroendocrine Differentiation: Report of a Case

A thyroid nodule with elevated plasma levels of calcitonin is usually suggestive of a medullary thyroid carcinoma (MTC); however, thyroid and extrathyroid conditions have been reported with elevated plasma calcitonin levels in the absence of MTC. We report the case of a patient with a thyroid nodule and an elevated basal plasma calcitonin level of 315 pg/ml (normal value <100 pg/ml) who underwent a left hemithyroidectomy. Interestingly, histopathological examination revealed a Hurthle-cell carcinoma with positive neuroendocrine (NE) markers such as calcitonin and synapthophysin, but not with chromogranin staining. Thus, we discuss the phenomenon of non-NE tumors showing positivity for NE markers.

Increased calcitonin level in thyroid nodules without medullary carcinoma

Basal calcitonin measurement is routinely performed in patients with a thyroid nodule to detect medullary carcinoma. However, increased calcitonin does not always correlate with medullary carcinoma. The aim of this study was to analyse increased calcitonin levels in patients without medullary carcinoma and to find out whether absence of this carcinoma can be predicted with certainty. From 1992 to 2003, 5018 patients with thyroid nodules underwent thyroid surgery. A retrospective analysis of preoperative increased calcitonin levels in 67 of these patients was performed. Pathology revealed medullary carcinoma in 16 patients (group I), micromedullary carcinoma in 13 (group II) and no medullary carcinoma in 38 (group III). In group III, 30 patients had C-cell hyperplasia. The mean basal calcitonin level was 6250 pg/ml in group I (39-62 500), 109.6 pg/ml in group II (10-728) and 25.5 pg/ml in group III (10.5-145). The mean pentagastrin-stimulated calcitonin level was 1074.1 pg/ml in group II (26-5700) and 67.6 pg/ml in group III (10-205). There is an overlap of thyroid C-cell pathology for medullary carcinoma, micromedullary carcinoma and C-cell hyperplasia that occurs when basal calcitonin is between 10 and 145 pg/ml and pentagastrin-stimulated calcitonin between 10 and 205 pg/ml. In these patients, since medullary carcinoma cannot be completely excluded, total thyroidectomy should be recommended.

Medullary Thyroid Cancer in a Patient with Hirschsprung Disease with a C609Y Germline RET-mutation

Medullary Thyroid Cancer in a Patient with Hirschsprung Disease with a C609Y Germline RET-mutation

Prospects of Remission in Medullary Thyroid Carcinoma According to Basal Calcitonin Level

Prediction of remission in medullary thyroid carcinoma (MTC) depends on histopathological information often unavailable before surgery. Simply requiring a venous blood sample, preoperative basal calcitonin levels may be a better indicator of remission. In this institutional series of 224 consecutive patients with MTC and elevated preoperative basal calcitonin levels, postoperative calcitonin levels normalized in 28 (62%) of 45 patients with node-negative MTC and in 18 (10%) of 177 patients with node-positive MTC. On multivariate analysis, preoperative basal calcitonin levels greater than 500 pg/ml best predicted the failure to achieve biochemical remission, followed by nodal metastasis and reoperative status. Cumulative rates of biochemical remission fell continuously with rising serum basal calcitonin in node-negative patients. Node-positive patients did not achieve biochemical remission when their preoperative basal calcitonin levels exceeded 3000 pg/ml. Nodal metastasis started emerging at basal calcitonin levels of 10-40 pg/ml (normal range, <10 pg/ml). Distant metastasis and extrathyroidal growth began appearing in patients with node-positive MTC at basal calcitonin levels of 150-400 pg/ml. There were no differences between patients with sporadic and hereditary MTC after adjusting for multiple testing. Preoperative basal calcitonin levels may thus help individualize the extent of surgery and postoperative follow-up intervals for MTC.

Angiography-proven liver metastases explain low efficacy of lymph node dissections in medullary thyroid cancer patients

Aim. To report the role of liver angiography in the staging of medullary thyroid cancer (MTC) patients. Material and methods. Sixty MTC patients with persistent or recurrent hypercalcitonemia ( n=49), a characteristic general symptom (diarrhea, n=4) or a normal basal calcitonin level without general symptoms ( n=7) were investigated by dynamic liver CT, MRI and angiography between 06/1998 and 06/2002. Results. Dual-phase CT and MRI investigations identified hepatic metastases with relatively low frequency (8/58 on MRI, and 7/60 on CT). Angiography indicated liver involvement in 54/60 cases. The hepatic metastases were typically multiple, hypervascular, small foci (only 13 foci measured ≥10 mm). With one exception significant disease progression was not observed over 5 years of follow-up. Conclusions. Liver angiography is a powerful tool to reveal hepatic metastases in MTC patients. Frequent, inoperable liver metastases in hypercalcitoninemic MTC patients demonstrate that secondary lymph node dissection is an inefficient technique for restoration of a normal calcitonin level.

Single Center Experience in Primary Surgery for Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare disease, and most studies are either based on small numbers or multicenter studies with their inherent difficulties. Since 1995, a total of 440 patients with MTC underwent surgery in our clinic. A primary operation was performed in 188 patients (43% of 440). In 60 patients, the primary operation was performed because of a germline RET mutation ("prophylactic surgery"). Most (84%, 158/188) of the patients had pathologic calcitonin levels. Notably, MTC was found in almost 10% (3/30) of patients with normal calcitonin levels. However, all patients with lymph node metastases (LNMs) had elevated calcitonin levels. Total thyroidectomy (TTx) was performed in all patients. Lymph node dissection (LND) was performed at various extensions: one-compartment LND in 35% (66/188), three-compartment LND in 31% (58/188), and four-compartment LND in 29% (22/188). In general, lymph node dissection increased the likelihood of complications. LNM and distant metastases (DM) correlated with the extent of the primary tumor (pT category). The presence of LNM ranged from 17% (pT1 tumor) to 100% (pT4 tumor), whereas the presence of DM ranged from 0% (pT1 tumor) to 81% (pT4 tumor). Biochemical cure (normal calcitonin levels) was obtained in 72% (137/188) of patients. All 60 patients undergoing prophylactic surgery (tumor stage pT0/pT1) were biochemically cured. In contrast, only 60% (77/128) of the remaining patients were cured. The data suggest that primary surgery should be scheduled as soon as possible to treat patients at a node-negative stage. In the case of normal basal and elevated stimulated calcitonin levels, TTx and cervicocentral LND is recommended. If the basal calcitonin level is elevated, LND should include the cervicolateral compartment.

Timing and Extent of Surgery in Patients with Familial Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia 2A‐related RET Mutations Not Affecting Codon 634

In hereditary medullary thyroid carcinoma (MTC), recommendations regarding timing and extent of surgery are mainly based on the data of patients with the codon 634 RET mutation, which is the most often affected codon. Little is known about whether these recommendations may also be applied to patients with less common RET mutations. We ascertained the data from 140 patients with FMTC/MEN2A-related RET mutation not affecting codon 634 who have been treated at three specialized centers. The several RET mutations found affected codons 611 (n = 17), 618 (n = 22), 620 (n = 17), 768 (n = 9), 790 (n = 24), 791 (n = 21), 804 (n = 23), and 891 (n = 7). For each codon, the age of the youngest patient with MTC only (41, 7, 18, 29, 13, 47, 20, and 15 years, respectively), MTC with lymph node metastases (46, 24, 21, 34, 46, 47, 50, and 76 years, respectively), and MTC with distant metastases (52, 69, 43, 68, 57, - , - , and 75 years, respectively) was determined. All patients with lymph node metastases had elevated basal calcitonin levels. Based on these data, a more individual recommendation regarding timing and extent of surgery can be given. Because neither gender nor the type of nucleotide substitution for a specific codon appeared to have a significant influence on the age of onset, this recommendation should be based on the affected codon, the age of the patient, and the calcitonin level. Recurrent laryngeal nerve palsy (n = 6) and hypoparathyroidism (n = 3) were rather rare and were found only in patients older than 30 and 43 years, respectively, giving evidence that surgery in young patients can be performed safely.

Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects.

Routine measurement of serum calcitonin (CT) has been recently proposed for all patients with neoplastic thyroid disease to detect clinically occult medullary thyroid carcinoma (MTC). Data on the prevalence of elevated CT levels in nonneoplastic thyroid disease or in healthy subjects have not been reported to date. Four hundred and fourteen consecutive patients with suspected thyroid disease and 362 healthy controls underwent thyroid examination with measurement of basal serum CT. Whenever serum CT was 10 pg/ml or more, a pentagastrin (PG) stimulation test was performed. Twenty-eight of 414 patients (6.8%) showed elevated basal serum CT levels, 15 of them with nonneoplastic thyroid disease, and the remaining 13 subjects with neoplastic thyroid disease. Four patients with abnormal PG testing (stimulated CT, > or = 100 pg/ml) were identified. Three of them had biochemical and sonographical evidence of thyroiditis. Elevated basal CT levels were significantly more frequent in patients with Hashimoto's thyroiditis (HT; P < 0.05). One female patient with HT had a 5-mm nodule, which was classified as MTC. None of the 6 out of 362 healthy controls with elevated basal CT (1.7%) presented an abnormal PG test. Our data suggest that basal CT measurements can be of use in the detection/screening of MTC not only in subjects with neoplastic thyroid disorders, but also in patients with immunological evidence of HT. They also confirm earlier reports on the essential value of PG stimulation testing, even when basal plasma CT levels are only modestly elevated, with regard to establishing the diagnosis of MTC or its premalignant associated conditions (micro-MTC and neoplastic C cell hyperplasia).

When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations?

Background Once familial medullary thyroid carcinoma gene carrier status is established, thyroidectomy must be performed in infancy for mutations in exon 10, but in familial medullary thyroid carcinoma with non-cysteine RET mutations, which is characterized by a late onset of C-cell disease, the appropriate timing of thyroidectomy is unclear. Methods We analyzed the cases of 76 patients who underwent thyroidectomy (mean age, 35.2 years); 66 patients underwent concomitant lymphadenectomy. Results Before the operation, 35 patients had abnormal basal calcitonin levels. Nine and 30 patients had negative or positive pentagastrin test results, respectively. We found normal thyroid in 4% of the patients, C-cell hyperplasia in 29% of the patients, medullary thyroid carcinoma in 67% of the patients (microscopic in 82.4%), and nodal metastases in 19.6% of the patients. The aggressiveness of the disease varied significantly between those patients with preoperative positive pentagastrin test results and those patients with high basal calcitonin levels, with a surgical cure rate of 60% and 34.3%, respectively. All patient who did not achieve cure had high basal preoperative calcitonin levels, which were related to macroscopic medullary thyroid carcinoma and nodal metastases in 5 of 9 patients. Conclusion Thyroidectomy should not be delayed until basal calcitonin level becomes abnormal, at which time advanced disease may be present. As soon as the pentagastrin stimulation test becomes abnormal, operation should be undertaken on early staged disease to achieve cure for the patient. When performed while pentagastrin stimulation test is still negative, thyroidectomy may be truly prophylactic and should be recommended at 5 to 6 years.

Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients

Background The surgical management and follow-up strategy in patients with medullary thyroid carcinoma (MTC) remain controversial because of the lack of data on the natural history of these tumors and their patterns of progression. Methods We reviewed the records of all patients who underwent a cervical operation for MTC between 1991 and 2002. Compartment-oriented surgery (COS) was performed to minimize the risk of cervical recurrence. Results We identified 92 consecutive patients who underwent a cervical operation for MTC: 80 had invasive MTC, and 12 had C-cell hyperplasia after prophylactic thyroidectomy for familial MTC. Ten (13%) of the 80 patients with invasive MTC presented with distant metastases and underwent COS to achieve local-regional control; cervical recurrence developed in none, but three have died of MTC. The remaining 70 patients underwent COS for primary (n = 23) or recurrent (n = 47) MTC. Disease recurred in 18 (26%) of these 70 patients at a median follow-up of 35 months, with 10 (14%) of the recurrences being cervical. Recurrent disease was associated with a basal calcitonin level of >250 pg/mL in all but four patients, two of whom showed tumor dedifferentiation. In contrast, only 5 (11%) patients without evidence of recurrence had basal calcitonin levels of >250 pg/mL at last follow-up. Conclusions Complete COS minimizes cervical recurrence. Radiographic evidence of recurrent disease is unlikely when the calcitonin level is ≤250 pg/mL. These data could be used to develop a logical, cost-effective treatment and follow-up strategy for patients with MTC.

Diagnóstico laboratorial do carcinoma medular de tiróide: calcitonina basal e testes de estímulo

A calcitonina é um hormônio secretado pelas células parafoliculares tiroideanas. O diagnóstico de carcinoma medular de tiróide (CMT) pode ser suspeitado a partir do encontro de níveis aumentados de calcitonina basal ou após testes de estímulos específicos. Neste sentido, a calcitonina caracteriza-se como um importante marcador tumoral para o diagnóstico e seguimento de pacientes portadores de CMT. Neste artigo, revisamos alguns tópicos referentes à utilidade da dosagem de calcitonina basal em pacientes portadores de nódulos de tiróide para rastreamento de CMT. Comentamos a respeito dos principais testes de estímulo para secreção de calcitonina disponíveis e finalizamos com algumas observações sobre os ensaios para dosagem de calcitonina.

Potential Absence of Prognostic Implications of Severe Preoperative Hypercalcitoninemia in Medullary Thyroid Carcinoma

To evaluate preoperative hypercalcitonine-mia further as a marker of prognosis in patients with medullary thyroid carcinoma (MTC). We reviewed the clinical and laboratory data in six patients (four men and two women, 39 to 76 years old)--three with sporadic MTC, one with familial MTC, and two with multiple endocrine neoplasia type 2A--who had preoperative basal serum calcitonin levels of 400 to 16,000 pg/mL (normal, 0 to 19). Pentagastrin stimulation was performed in patients who had preoperative basal calcitonin levels less than 1,000 pg/mL, and responses ranged from 2,600 to 8,500 pg/mL. Thyroidectomy revealed intrathyroidal MTC in four patients; MTC and nodal metastatic lesions were present in two. The tumor cells were immunoreactive with anti-calcitonin immunoperoxidase staining. Serum calcitonin and carcinoembryonic antigen levels were normal postoperatively. In serial postoperative evaluation during a follow-up period of 2 to 9 years, stimulated peak plasma calcitonin levels after pentagastrin or calcium infusion were normal (in five patients) or near normal (in one patient), without clinical evidence of recurrent disease. The two patients with nodal metastatic disease have had normal calcitonin levels during a mean duration of follow-up of approximately 3 years. Pronounced preoperative hypercalci-toninemia does not necessarily preclude a favorable short-term outcome in patients with MTC.

Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging.

Imaging-detected relapses are observed in a significant proportion of patients with medullary thyroid carcinoma (MTC) with normal postoperative imaging studies. The aim of this study was to search for prognostic factors of imaging-detected relapse. This retrospective study was performed in 63 consecutive MTC patients with normal postoperative medical imaging. After surgery, the basal calcitonin (CT) level was undetectable in 35 patients and elevated in 28. During follow-up, 18 patients developed a clinical or imaging-detected relapse (29%) in the neck and/or at distant sites: 15 had an elevated postoperative basal CT level and three had an undetectable postoperative basal CT level. At multivariate analysis, the significant parameters predictive of imaging-detected relapse were the postoperative plasma CT level and the tumour extension (pT). The 3- and 5-year relapse-free survival rates were 94 and 90% in patients with an undetectable postoperative basal CT level, and 78 and 61% in patients with a detectable basal CT level (P<0.05). The 3- and 5-year relapse-free survival rates were 92 and 85% in the pT1–3 patients, and 57 and 46% in the pT4 patients (P<0.01). These results show that postoperative CT level and tumour extension are critical prognostic factors for the identification of patients at a high risk of relapse.

Molecular and Biochemical Screening for the Diagnosis and Management of Medullary Thyroid Carcinoma in Multiple Endocrine Neoplasia Type 2A

Patients with Multiple Endocrine Neoplasia (MEN) type 2A are at risk for early medullary thyroid carcinoma (MTC). We performed different screening tests for MTC--a recently reported biochemical screening test using omeprazole-induced calcitonin (CT) stimulation and DNA analysis--in fifteen members of two non-consanguineous Brazilian families with MEN 2A. RET proto-oncogene analysis was carried out by direct DNA sequencing of PCR-amplified products for exons 10 and 11. Family 1 showed a germline mutation (C634Y) in three individuals; a sister and a brother with symptomatic MTC; the former also presented with pheochromocytoma and hyperparathyroidism, and her son was a nine-year-old boy of previously unknown status. Family 2 showed the C634R mutation only in the index case, who presented with cutaneous lichen amyloidosis in addition to MTC, pheochromocytoma and hyperparathyroidism. Neither her parents nor her four brothers showed this genetic abnormality, suggesting a de novo RET proto-oncogene mutation in this patient. The controls and patients presented normal basal gastrin levels and a significant increase after omeprazole. Basal CT levels were elevated in patients with MTC and undetectable in control and asymptomatic family members. No subject showed any increase in CT levels after omeprazole treatment. In conclusion, the two most frequent RET proto-oncogene mutations in MEN 2A are present in Brazilian families. In addition, the specificity of basal and omeprazole-stimulated calcitonin is rather limited, and the efficacy of the omeprazole test still needs to be systematically examined. Therefore, RET proto-oncogene analysis must be the first choice for a screening procedure to identify gene carriers in MEN 2A family members and to permit early prophylactic treatment of MTC.

Unusual clinical manifestation of pheochromocytoma in a MEN2A patient

A case of unusual clinical manifestation of pheochromocytoma in a type 2A multiple endocrine neoplasia (MEN2A) patient is presented. A 27-year-old man affected by MEN2A syndrome, complaining of anxiety and depression, was admitted in our Division. Past medical history included a total thyroidectomy for medullary carcinoma in 1985, and left adrenalectomy for pheochromocytoma in 1994. Blood pressure was 130/ 85 mmHg without orthostatic hypotension and pulse rate was 72 beats/min. Laboratory data revealed thyroid hormones and carcinoembryonic antigen (CEA) in the normal range and high basal serum calcitonin levels (158 pg/ml). Plasma catecholamines and vanillylmandelic acid resulted in normal levels but epinephrine/norepinephrine ratio was elevated (0.65). The glucagon stimulation test showed positive clinical and biochemical response. Magnetic resonance imaging (MRI) and meta-iodobenzylguanidine (MIBG) scintiscan confirmed the presence of bilateral adrenal masses. Bilateral adrenalectomy by laparoscopic anterior approach was performed. Histology was consistent with adrenal pheochromocytomas. After surgical approach, psychiatric findings disappeared and did not recur at follow-up in spite of no medication for two years. In conclusion, bilateral pheochromocytoma is more frequent in MEN2A syndrome and probably understimated if the follow-up is not prolonged. In these cases clinical features are often aspecific and basal hormonal data may be normal in a great number of patients. Therefore long-term observation is justified in these patients. Pheochromocytoma was described as the "great mimic" for the numerous subjective manifestations. Differential diagnosis among typical features of neuropsychiatric disorders and pheochromocytoma must be considered.

High plasma amylin/islet amyloid polypeptide levels in patients with residual medullary thyroid carcinoma after total thyroidectomy.

We have previously reported that amylin/islet amyloid polypeptide (IAPP) mRNA is detected in a substantial subset of medullary carcinomas of the thyroid (MTCs). The aim of this study was to determine if the amylin/IAPP gene is expressed as the IAPP peptide in MTC tissues. In 10 patients with a histological diagnosis of MTC and with persisting or recurrent disease (basal calcitonin levels >250 pg/ml), the fasting serum insulin and plasma glucose, IAPP and calcitonin levels were measured and compared with those of 18 normal control subjects matched for age and body mass index. IAPP expression was studied by immunohistochemistry in MTCs and lymph-node metastasis tissues. Seven of ten MTC patients had abnormally elevated IAPP levels. Plasma IAPP and serum insulin levels were correlated in both patients and controls, but the slope of the regression line was significantly higher for MTC patients. IAPP staining was detected in four out of 12 random MTC samples and in two out of five lymph-node metastases, using immunohistochemistry. These results indicate that MTC cells express IAPP at the peptide level and that this raises the peripheral plasma levels. Further studies may reveal whether this is a feature of malignant disease.

Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma

Calcitonin is a sensitive marker for medullary thyroid carcinoma. Normalisation of calcitonin levels following resection of medullary thyroid carcinoma has been described after a few hours; however, it may be observed more than 4 weeks after surgery. The aim of this study was to correlate the postoperative calcitonin kinetics with preoperative calcitonin levels and tumour stage. Furthermore, we wanted to test the prognostic impact of the calcitonin kinetics. Therefore, only patients with postoperative normalisation of calcitonin levels (biochemical cure) were included in this study. Fourteen biochemically cured patients were analysed, including measurement of postoperative basal and pentagastrin-stimulated calcitonin concentration. With respect to the time of postoperative basal calcitonin normalisation, patients were classified into two groups: (A) patients with normalisation of basal calcitonin levels within 24 h and (B) patients with normalisation of basal calcitonin levels later than 24 h postoperatively. Eight patients were found to have normalisation of basal calcitonin levels within 24 h (group A). In the remaining six patients (group B), the period to normalisation of basal calcitonin levels varied from 6 days to 14 days and longer. There were no differences between the two groups with regard to tumour size, number and pattern of lymph node metastases and tumour stage. However, preoperative basal calcitonin levels were significantly different (258 ng/ml vs 955 ng/ml, P<0.01). In the group with slow-decreasing calcitonin levels, no strong correlation between the preoperative level and the postoperative time to normalisation of basal calcitonin levels could be established, which may be due to the small number of patients. After a median follow-up of 21 months, no patient developed tumour recurrence. However, an increased basal calcitonin level was observed in one patient from group B. All other patients had normal basal and peak calcitonin levels. Using a highly sensitive calcitonin assay, we demonstrated that normalisation of basal calcitonin levels may be delayed in patients suffering from medullary thyroid carcinoma. The lack of correlation of preoperative levels and the time to normalisation of the basal calcitonin levels, as well as the positive pentagastrin test in some of the patients, argues that this phenomenon is not simply due to prolonged biochemical calcitonin elimination. Nevertheless, a prognostic influence could not be shown in this study due to the short follow up-period. Further investigations and a longer follow-up are necessary to determine the nature and the prognostic impact of delayed normalisation of calcitonin levels.

Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients.

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.