Elevated Plasma Calcitonin Research Articles

Clinical and biochemical alterations associated with excess calcitonin in a dog with medullary thyroid carcinoma

AbstractWe present a 10‐year‐old mongrel dog with progressive weight loss, polyuria and polydipsia. Physical examination revealed poor body condition, systemic hypertension (on average 165 mmHg) and a cervical mass that was confirmed by ultrasound in the right thyroid lobe (diameter 4.0 cm). Blood biochemistry on two different days revealed a low ionised calcium concentration (1.1 and 0.81 mmol/L; reference range: 1.1–1.3 mmol/L) associated with an elevated plasma calcitonin concentration in the same sample (44.8 and 49 pg/mL; reference range: <2 pg/mL). A low urine specific gravity (1.012) was also found. Total thyroxine concentration was low, corresponding to euthyroid sick syndrome. Hypercalcitoninemia, hypocalcaemia and clinical signs resolved after an uncomplicated right thyroidectomy. Positive staining of the neoplasm for calcitonin on immunohistochemistry confirmed a medullary thyroid carcinoma. This is the first report describing the clinical signs and biochemical alterations associated with excess calcitonin in a dog with medullary thyroid carcinoma confirmed by immunohistochemistry.

Molecular-genetic diagnosis of a Bulgarian family with multiple endocrine neoplasia, type IIA

INTRODUCTION : Multiple Endocrine Neoplasia (MEN) is a rare autosomal dominant disease with frequency 1:30 000 and it is classified in 3 subtypes: MEN 2A (Sipple syndrome), familial medullary thyroid carcinoma (FMTC), MEN 2B. The MEN 2A subtype constitutes approximately 70%-80% of cases of MEN 2. The onset age of the MEN 2A is prior to age 35 years. MEN 2A has an increased risk for parathyroid hyperplasia or adenoma. The clinical diagnosis is suspected when at least 2 specific endocrine tumors are detected in one patient or close relatives (MTC, pheochromocytoma, parathyroid adenomas). MTC is suspected in case of increased serum levels of calcitonin. The biochemical phenotype of MTC is revealed between age 5 and 25 (mean age 15 years). The tumor formation in the neck area is between age of 15 and 20 (2). Although there is controversy surrounding the definition of CCH, its utility to identify or confirm MEN 2 has been essentially replaced by RET (REarranged during Transfection) protooncogene testing. This allows the early surgery interventions, proper genetic counseling and prenatal diagnostics. MATERIAL AND METHODS : We report on a Caucasian male with complains of general weakness and weight loss (10 kg for 2 month). The patient`s mother has been diagnosed at 47 as bilateral pheochromocytomas and struma nodosa and died at age of 51. In the index patient abdominal ultrasound examination with biopsy of adrenal glands and histological analysis revealed pheochromocytoma on the right side; elevated plasma calcitonin concentration and US scan with biopsy of thyroid tissue detected medular thyroid cancer. The index patient has two elder brothers - it turned out that one of them had been surgically treated for medular thyroid cancer in the past; bilateral pheocromocytomas were detected in the family screening process. RESULTS AND CONCLUSION : MEN 2A diagnosis was suspected and we performed sequencing of RET protooncogene. The genetic analysis of the family affected members revealed c.1902C>G, p.Cys634Trp heterozygous mutation. Unfortunately, two kids in the families of 2 of the brothers have also inherited the mutation. All adult family members were offered genetic counseling. The standard therapy and the prophylactic thyroidectomy include the surgical removal of the thyroid gland, followed by parathyroid gland autotransplantation. In case codon 634 mutation the surgery is recommended before age of 5 years. All affected relatives are going through monitoring for residual disease. The screening protocol includes plasma levels of calcitonin. The stimulation tests are more sensitive than calcitonin measurements alone so they are recommended.

Medullary thyroid carcinoma and biomarkers: past, present and future

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Calculation and Validation of a Plasma Calcitonin Limit for Early Detection of Medullary Thyroid Carcinoma in Nodular Thyroid Disease

The early diagnosis of medullary thyroid carcinoma (MTC) is crucial for effective therapy. Elevated plasma calcitonin concentrations (pCT-Cs) are generally a specific and sensitive indicator for C-cell hyperplasia or MTC. The presence of thyroid nodules raises the possibility of MTC. Hence, in endemic goiter regions, there is a need for information regarding the pCT-C values that are indicative of C-cell hyperplasia or MTC. The aim of this study, therefore, was to determine an upper pCT-C to distinguish patients with and without MTC in a collective with nodular thyroid disease, and to give an estimation of the prevalence of MTC in an endemic goiter area. Basal pCT-C was measured in 21,928 patients with thyroid nodules living in central Germany, an area with endemic goiter due to previous iodine deficiency. In 218 subjects with pCT-Cs exceeding 10 ng/L, stimulated pCT-C was additionally determined, as suggested by the German consensus recommendation. A nominal normal range for basal pCT-C was calculated with data from 21,900 subjects without known MTC. The predicted upper limit was then validated using the known diagnoses of 376 patients with pCT-Cs exceeding 10 ng/L, 28 of whom presented with MTC. For basal pCT-C, calculation of the three-sigma borders after logarithmic transformation revealed upper limits of the nominal normal range of 14.6 ng/L in females and 32.8 ng/L in males, respectively. However, three male patients with small MTCs had basal pCT-Cs between 15 and 33 ng/L. None of the patients with MTC had a basal pCT-C below 15 ng/L or an increase in pCT-C after pentagastrin stimulation that was less than 80 ng/L. In the basal pCT-C range between 15 and 50 ng/L (n = 192; eight with MTC), the positive predictive value for the detection of MTC was 4% in our group. Applying an upper limit for basal pCT-C of 15 ng/L in both sexes, 329 of the total of 21,928 patients exceeded this range. Among these, the final outcome is known in 231 subjects, including all 28 MTCs. An upper limit of 15 ng/L instead of 10 ng/L for basal pCT-C is able to detect all MTC and reduce false-positive cases. The prevalence of MTC in nodular thyroid disease in our group was approximately 1.8 per thousand.

Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity.

In an evaluation of 213 patients from 15 kindreds with familial medullary thyroid carcinoma (MTC), we detected 41 subjects from two kindreds (L and O) who had MTC but no extra-thyroidal manifestations (hyperparathyroidism, phaeochromocytomas or mucosal neuromas) of multiple endocrine neoplasia (MEN) type IIa or IIb. In screening 178 members of the L and O kindreds, we found no evidence that any of them had died from MTC. To assess whether the malignancy was relatively indolent in these families, 20 selected subjects from the two kindreds were compared with 33 MEN IIa subjects. Both groups had clinically occult disease which was diagnosed biochemically by documenting elevated plasma calcitonin (CT) levels following stimulation with intravenous calcium and pentagastrin. There were no differences in the peak stimulated plasma CT levels at the time of diagnosis (1055 +/- 236 pg/ml versus 1096 +/- 191 pg/ml) or the incidence of regional lymph node metastases (0/20 versus 1/33) in the two groups. The mean age at diagnosis, however, was significantly higher in patients of the L and O kindreds than in patients with MEN IIa (43.1 +/- 3.4 years versus 21.1 +/- 2.2 years; P less than 0.001) indicating that in the two kindreds the MTC either developed at a later age or grew more slowly. This study demonstrates that MTC may occur in a familial pattern distinct from its presentation as MEN IIa or MEN IIb. In this setting it appears to be the least aggressive form of MTC yet described.

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.

Primary hereditary medullary thyroid carcinoma--C-cell morphology and correlation with preoperative calcitonin levels.

Early thyroidectomy offers an opportunity of preventing the development of medullary thyroid carcinoma (MTC) in patients at risk for hereditary MTC. We investigated the thyroid glands of 32 patients with hereditary MTC to identify the changes in C-cell morphology and to correlate these with plasma calcitonin (CT) levels and with clinical data. The entire thyroid gland was processed for histological examination including immunostaining for CT. All glands revealed C-cell hyperplasia (CCH), and MTC was found in 21 patients (66% of 32, youngest patient 6 years, youngest with lymph node metastases [LNM] 17 years). The transition from CCH to MTC was characterized by destruction of the follicular basement membrane and by diminished intensity of CT immunostaining. Normal plasma CT levels after provocation with pentagastrin were found only in patients with CCH. Basally elevated plasma CT levels were restricted to MTC. LNM were only found in multifocal tumours at least 4 mm in diameter. It is not yet clear whether or not CCH in patients at risk for hereditary MTC is a neoplastic change, but in these patients the term 'C-cell hyperplasia' is of doubtful value. All MEN gene carriers reveal CCH, and almost all of them will develop multifocal MTC, so that CCH is probably a precursor lesion of an indubitably malignant tumour. Prophylactic thyroidectomy is justified at the age of 6 to anticipate development of a MTC. Lymphadenectomy is necessary in children if they are older than 10 years or have elevated plasma CT levels.

Enhanced bilateral somatostatin receptor expression in mediastinal lymph nodes ("chimney sign") in occult metastatic medullary thyroid cancer: a typical site of tumour manifestation?

In medullary thyroid cancer (MTC), post-surgically elevated plasma calcitonin and/or carcinoembryonic antigen levels frequently indicate persisting metastatic disease, although conventional diagnostic procedures fail to localize the responsible lesions (occult disease). Somatostatin analogues have been used successfully in disease localization, but recently concerns have been raised that increased thoracic uptake of indium-111 pentetreotide in patients with previous external beam irradiation may represent a false-positive finding, caused by post-irradiation pulmonary fibrosis. We recently examined seven patients with metastatic MTC by somatostatin receptor scintigraphy (six with occult and one with established disease). In four patients, all of whom had stable or slowly rising tumour marker levels over several years, a chimney-like bilateral mediastinal uptake of indium-111 pentetreotide was found. In two patients with persisting hypercalcitonaemia immediately after primary surgery, supraclavicular lymph node metastases were identified as the responsible lesions. None of these seven patients had prior external beam radiation therapy. In two cases, histological confirmation was obtained. In one patient, disease progression could be shown during follow-up. These data suggest that bilateral mediastinal lymph node involvement is a typical site of disease in slowly progressing occult metastatic MTC; the "chimney sign" may represent a typical finding with somatostatin analogues in such cases. Therefore, we believe that even in the case of prior external beam irradiation, mediastinal uptake of octreotide might represent metastatic MTC rather than radiation fibrosis.

Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels

Patients operated on for medullary thyroid carcinoma (MTC) frequently have persistent elevated plasma calcitonin concentrations after operation, indicating remaining tumor. The plasma calcitonin concentration in a patient with MTC roughly reflects the endogenous tumor burden. The only effective treatment for MTC is surgical. The decision about whether a patient with persistent MTC should have a repeat operation would be influenced by knowledge of the natural course of the disease. Forty patients with persistently elevated peak plasma calcitonin concentrations after thyroidectomy for MTC were monitored for a mean of 6 years. Serial determinations of plasma calcitonin levels were obtained before and after intravenous injection of calcium and pentagastrin. At the first postoperative test 63% of the patients had undetectable basal calcitonin values, although their stimulated plasma calcitonin concentrations were elevated. The mean annual increase in stimulated plasma calcitonin concentrations was 117%, but plasma calcitonin concentrations were stable in three patients and decreased in one patient. Five patients are known to have experienced distant metastases. MTC is a progressive disease in most patients with persistent hypercalcitoninemia after thyroidectomy. Stimulated peak plasma calcitonin levels are more meaningful than basal levels in the serial postoperative evaluation of patients with persistent hypercalcitoninemia after thyroidectomy for MTC.

Clinical Screening as Compared with DNA Analysis in Families with Multiple Endocrine Neoplasia Type 2A

Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene. Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene. Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia. Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Current Perspectives on the Diagnosis and Management of Patients with Multiple Endocrine Neoplasia Type 2 Syndromes

Patients with MEN 2A, MEN 2B, and familial non-MEN medullary thyroid carcinoma (MTC) inherit MTC in an autosomal dominant fashion. This malignancy has been diagnosed previously by detecting elevated plasma calcitonin levels, a tumor marker for MTC, following the intravenous administration of secretagogues. Although the study of large pedigrees with MEN 2A, using highly informative flanking markers and linkage analysis, are highly accurate in predicting the inheritance of the disease, the method is indirect and somewhat cumbersome. Mutations in the RET proto-oncogene have been identified independently in patients with MEN 2A and familial medullary thyroid carcinoma. Even though the RET mutations are inherited with disease, there is no direct evidence that the mutations cause the MEN 2 syndromes. The usefulness of molecular methods in the diagnosis and treatment of patients with these syndromes is discussed, and a strategy for deciding operative intervention is presented.

Reoperation for recurrent or persistent medullary thyroid cancer.

Initial operations for medullary thyroid cancer (MTC) frequently do not eradicate all disease, as evidenced by persistently elevated levels of stimulated plasma calcitonin. Thirty-two patients with MTC and elevated stimulated plasma calcitonin levels after thyroidectomy were studied between 1990 and 1993. Thirty-five repeat neck explorations and microdissections were performed. Four patients also underwent a median sternotomy and mediastinal dissection. In nine patients (group 1), stimulated plasma calcitonin levels were undetectable after reoperation, whereas in 13 cases (group 2) the calcitonin levels decreased by 40% or more. In 10 cases (group 3) the CT levels did not decrease. Primary tumors that exhibited invasive features (invasion of adjacent structures or extranodal or extracapsular spread) were found more often in patients from group 3 than in patients from groups 1 or 2 (p < 0.05, Fisher's exact test). Reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The data also suggest that patients whose primary MTC has invaded tissues beyond the thyroid gland or a lymph node capsule are less likely to benefit from repeat operation.

Results of long-term continuous subcutaneous octreotide administration in 14 patients with medullary thyroid carcinoma.

Treatment by octreotide has been suggested in medullary thyroid carcinoma patients with post-surgery metastases. The purpose of this study was to evaluate if the tumoral regression could be improved by a high dose and by prolonged octreotide treatment. Fourteen thyroidectomized patients were studied. All patients had persistently elevated plasma calcitonin levels with normal or elevated carcino-embryonic antigen levels. Five hundred micrograms/day of octreotide were administered by continuous subcutaneous infusion for 90 days. Plasma calcitonin and carcino-embryonic antigen levels were determined at days -30, -20, -2, -1, 0, +30, +60, +90, +120; morphological extension was evaluated every month. Continuous infusion of octreotide did not induce any significant decrease of calcitonin levels, or any morphological improvement, and had no major undesirable effect. However, in 4/14 patients calcitonin levels fell during treatment (-43, -50, -15, -20%), and in 9 patients calcitonin increased (+22 to +130%) after cessation of therapy. Biological or morphological parameters of medullary thyroid carcinoma are not significantly improved in a large series of patients treated by octreotide.

Cholecystokinins but not gastrin-17 release calcitonin from thyroid C-cells in the rat

Subcutaneous injections of gastrin-17, cholecystokinin-39, cholecystokinin-8 (sulfated and non-sulfated forms), cholecystokinin-4 or pentagastrin induced hypocalcemia in rats. The hypocalcemia was associated with calcitonin release for pentagastrin and the cholecystokinins but not for gastrin-17, even at very high doses. Permanent hypergastrinemia, induced by surgical removal of the acid-producing part of the stomach (fundectomy) or by treatment with high doses of omeprazole, a blocker of acid secretion, was not accompanied by elevated plasma calcitonin. Long-lasting hypergastrinemia is known to cause hyperplasia of gastrin-sensitive endocrine cells in the rat stomach while hypogastrinemia does the reverse. In antrectomized rats, having low serum gastrin, and in fundectomized rats, having high serum gastrin, the serum calcitonin concentration, the thyroid calcitonin content and the number of C-cells remained as in sham-operated controls two months after the operations. We conclude that neither exogenous nor endogenous gastrin stimulates calcitonin secretion in the rat and that long-standing hypo- or hypergastrinemia is without effect on the number of thyroid C-cells. Our results, however, do not exclude the possibility that the cholecystokinins might act as calcitonin secretagogues in the rat although such a role remains to be established.

Metastatic Medullary Thyroid Carcinoma in Young Children with Mucosal Neuroma Syndrome

Multiple endocrine neoplasia, type 2b (MEN 2b) is a disorder characterized by a distinct phenotype and a predisposition for medullary thyroid carcinoma (MTC) and pheochromocytoma. Two siblings aged 3 and 6 years with MEN 2b, who had elevated plasma calcitonin levels suggesting the presence of MTC are described. Microscopic foci of MTC were found in their thyroid glands and the glands were removed. In the younger child, a metastatic focus was present in a cervical lymph node. Of 12 previously reported children with MEN 2b and MTC who were less than 10 years of age at diagnosis, five had metastases. One of the present patients is the youngest described with this complication. The high frequency of metastases in very young patients with this syndrome has not been emphasized previously. These findings indicate the need for early diagnosis of MEN 2b and the importance of thyroidectomy at the earliest possible age when MTC is suspected by calcitonin screening tests.

Hypercalcitoninaemia in Medullary Carcinoma of the Thyroid and Other Malignancies: Value of Calcitonin as Tumour Marker

Elevated plasma calcitonin was detected by radioimmunoassay in 19 of 99 unselected cancer patients (19%). The frequency of hypercalcitoninaemia in patients with tumours of lung, uterus, gastrointestinal tract, and urinary bladder was about 40%, in carcinoma of the breast 18%, and in carcinoma of the skin 4%. In 8 patients with bone metastases, 4 were hypercalcitoninaemic. None of 19 patients with non-malignant disorders had elevated plasma calcitonin. The highest plasma calcitonin level in cancer patients was 8200 ng/l. Urinary cyclic AMP was elevated in patients with hypercalcitoninaemia as compared with patients with normal plasma calcitonin. All 6 patients with medullary carcinoma of the thyroid had very high plasma calcitonin levels: more than 50000 ng/l in five and 30000 ng/l in one patient. Of the family members of these patients, raised plasma calcitonin was detected after stimulation with oral alcohol in 6 of 12. It is concluded that plasma calcitonin levels in excess of 10000 ng/l suggest the presence of medullary carcinoma of the thyroid, while levels below 10000 ng/l have a poor diagnostic value but should alert the clinician to look for a possible malignancy.

Gastrin Responses to a test meal in patients with familial medullary thyroid carcinoma.

The serum gastrin response to a standard test meal was evaluated in patients with familial medullary thyroid carcinoma (MTC) and in normal subjects. Patients with MTC and elevated plasma calcitonin levels had a lower gastrin response to the test meal than did normal persons or MTC patients who had normal calcitonin levels postthyroidectomy. There was no significant difference between the mean gastrin response of the normal group and that of the MTC patients with normal calcitonin levels. The serum gastrin response was studied before and after thyroidectomy in four patients. In all four, the post-operative response was greater than the preoperative one . We conclude that patients with MTC may have reduced gastrin responses to a test meal. This effect may be related to circulating calcitonin, somatostatin, or other factors related to familial MTC.

Plasma calcitonin as a marker of disease activity in patients with small cell carcinoma of the lung.

To evaluate the usefulness of plasma calcitonin as an index of tumor burden and disease activity, we undertook a prospective study of serial calcitonin measurements in a group of patients with small cell carcinoma of the lung from diagnosis throughout a period of intensive therapy. Plasma calcitonin was significantly elevated in 84% of patients with extensive small cell carcinoma of the lung and was not elevated in patients with limited disease at the time of diagnosis. The elevated values fell significantly in response to chemotherapy and radiation therapy, and reflected regression of followable disease and improvement in clinical status. A significant correlation existed between plasma calcitonin and extent of disease. Relapse was generally associated with an increase in elevated plasma calcitonin levels, and calcitonin appeared to reflect tumor burden. The serial measurement of plasma calcitonin is useful in the management of the patient with small cell carcinoma of the lung.

Medullary carcinoma of the thyroid in the multiple endocrine neoplasia IIA syndrome.

Clinical, biochemical, and morphologic parameters in 72 patients with familial medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia IIA (MEN IIA) were reviewed. Sixty-nine patients had undergone total thyroid resection. In 27 patients (Group I) the thyroid tumors were smaller than 0.7 cm in diameter; five of these patients had C-cell hyperplasia alone. In 19 patients (Group II) tumors ranged from 0.7 to 1.5 cm, and in 26 patients (Group III) they were larger than 1.5 cm. The mean ages at surgery were 19.6 years (Group I), 33.7 years (Group II), and 32.2 years (Group III). Regional lymph node metastases occurred less often in patients of Group I, 4/20 (20%) and Group II, 4/13 (30%) than in those of Group III, 14/17 (82%) [p = 0.0001]. Elevated postoperative plasma calcitonin levels, indicative of residual MTC, were observed less frequently in patients in Group I, 6/27 (22%) and Group II, 6/15 (50%) than in Group III, 11/15 (73%) [p = 0.005]. All of the patients in Group I and Group II are alive (mean follow-up of 3.5 years and 6.0 years following surgery), whereas 6/26 (23%) Group III patients have died of metastatic MTC, three within 2 years of initial diagnosis. Histologic features varied with tumor diameter. All tumors from patients in Group III contained amyloid, while the majority of those from patients in Group I had an infiltrative configuration and 9/22 tumors lacked amyloid. Among neoplasms from patients in Group III, mitotic figures correlated with distant metastases or death from tumor. Only 1/16 patients who died from MTC had a distinctive tumor morphology, namely a prominent component of small cell anaplastic carcinoma. Early detection of minimal MTC in MEN IIA family members offers the best chance of curing patients with this potentially fatal lesion.