Increased calcitonin level in thyroid nodules without medullary carcinoma

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.     

Primary hyperparathyroidism, C-cell hyperplasia and papillary thyroid carcinoma in a patient with RET germline polymorphism S836S

BACKGROUND: In most examined populations the RET germline polymorphism S836S is found in about 3.6% of the normal population but in about 9% of patients suffering from sporadic C-cell hyperplasia or medullary thyroid carcinoma. The polymorphism S836S is thought to be involved in the development of sporadic medullary thyroid carcinoma. CASE PRESENTATION: We report a 48-year-old woman suffering from primary hyperparathyroidism (parathormone 121-166 pg/ml, normal <72), bilateral diffuse and nodular C-cell hyperplasia (calcitonin after pentagastrin administration 156 pg/ml, normal <4.6), and papillary thyroid carcinoma. Two commercial analyses of RET did not reveal any germline mutation within the known hot spots. However, sequencing revealed the presence of the RET polymorphism S836S. Following total thyroidectomy and removal of two hyperplastic parathyroid glands parathormone decreased to 51 pg/ml and calcitonin was no longer detected. CONCLUSIONS: The pathogenetic importance of the RET polymorphism S836S is still obscure. However, according to the published overrepresentation of the RET polymorphism S836S in patients suffering from apparent sporadic medullary thyroid carcinoma, it is conceivable that it also plays a role in multiglandular endocrine disease.     

Thyroid Venous Catheterization in the Early Diagnosis of Familial Medullary Thyroid Carcinoma

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520±635 pg/ml) and C (6322±2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.     

Prophylactic thyroidectomy in MEN IIA: does the calcitonin level correlate with tumor spread?

Background: The fate of patients with multiple endocrine neoplasia of type II A (MEN II A) is determined by medullary thyroid carcinoma, which occurs in all cases. This has led to the therapeutic concept of prophylactic thyroidectomy in affected family members with the goal of removing the thyroid before the manifestation of carcinoma. We investigated a prophylactically thyroidectomized MEN II A population to determine whether the highly specific and sensitive tumor marker calcitonin correlates with tumor spread. Patients and methods: Fifteen patients with MEN II A (aged 4 – 24 years) who had undergone prophylactic thyroidectomy since 1990 were included in the study. Baseline and pentagastrin-stimulated calcitonin levels were preoperatively determined in all cases. The indication for surgery was established on the basis of pathologic calcitonin levels in the first seven patients and on the basis of detected RET proto-oncogene mutation in the other eight patients. Bilateral central lymphadenectomy was performed in all patients in addition to thyroidectomy. Results: Histology demonstrated C-cell hyperplasia in five patients (aged 4 – 13 years), unilateral medullary microcarcinoma in six (aged 9 – 17 years) and a bilateral medullary microcarcinoma in three cases (aged 17 – 24 years). One 9-year-old boy with bilateral microcarcinoma already had a lymph node metastasis. The mean baseline calcitonin level correlated with the histologic findings (r = 0.71, P = 0.003) but there was no correlation between pentagastrin-stimulated calcitonin levels and histology (r = 0.21, P = 0.47). Conclusion: In MEN II A patients undergoing prophylactic thyroidectomy, baseline but not stimulated calcitonin levels already correlate with the histologic tumor stage at the stage of clinically occult C-cell hyperplasia or medullary microcarcinoma. However, biochemical screening cannot reliably discriminate the transition from C-cell hyperplasia to invasive microcarcinoma. Individuals with MEN II A should therefore undergo early prophylactic thyroidectomy once the diagnosis is confirmed by molecular genetic testing. Received: 27 January 1998     

Total thyroidectomy for occult familial medullary carcinoma of the thyroid in children

Experience with 17 children in one kindred with familial medullary carcinoma of the thyroid and pheochromocytoma has demonstrated the utility and validity of periodic provocative testing by calcium infusion or pentagastrin injection in the identification of children with early medullary carcinoma of the thyroid or its premalignant precursor, C-cell hyperplasia. In these 17 patients with two consecutive elevations of calcitonin levels greater than 0.55 ng/ml after stimulation all but one have had MTC or CCH at operation. Total thyroidectomy has been well tolerated and can be performed with an acceptably low incidence of complications in this group of patients.     

Can Sporadic Medullary Thyroid Carcinoma Be Biochemically Predicted? Prospective Analysis of 66 Operated Patients with Elevated Serum Calcitonin Levels

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of ≤ 30 pg/ml and for sCT of ≤ 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of ≤ 30 pg/ml or sCT ≤ 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.     

Familial nonmultiple endocrine neoplasia medullary thyroid carcinoma: an evolving clinical entity.

BACKGROUND. A rare kindred of familial nonmultiple endocrine neoplasia medullary thyroid carcinoma arising from a 73-year-old proband case is reported to further define this distinct entity. METHODS. Twenty-four family members across four generations, four with medullary thyroid carcinoma (MTC) and two with C-cell hyperplasia (CCH), were studied. RESULTS. Basal calcitonin levels were elevated in three patients with MTC and were normal in one patient with microscopic MTC and two patients with CCH who had persistent subtle elevation in calcium and/or pentagastrin-stimulated calcitonin levels. One patient had unilateral MTC without CCH. Associated abnormalities included papillary carcinoma (2), thyroiditis (4), adenoma (2), and colloid nodule (1). Minimum treatment was total thyroidectomy. Two patients with MTC and marked hypercalcitonemia have recurrent disease at 2.5-year and 11-year follow-up. Two patients with MTC and normal or minor elevations in basal calcitonin and two with CCH had normal provocative calcitonin testing at 6 to 18 months follow-up. CONCLUSIONS. Unilateral MTC without CCH and MTC in the elderly do not preclude a familial cause. Microscopic MTC or CCH may be seen with subtle elevations in stimulated calcitonin levels, and recognition allows for curative thyroidectomy. Other apparent dominant thyroid pathologic conditions may occur concomitantly with familial medullary thyroid carcinoma and thus routine calcitonin, and immunohistochemical testing should be performed in patients with an appropriate family history.     

Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy

Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.     

Reversibility of ''Secondary Hypercalcitoninemia'' After Kidney Transplantation

Whether the increase of calcitonin (CT) concentration in patients with chronic kidney disease (CKD) is reversible or not after kidney transplantation is not known. We examined the effect of kidney transplantation on basal and pentagastrin-stimulated CT in CKD patients with elevated screening CT levels. Before transplantation, the median basal CT concentration of 17 patients was 31 pg/mL (13-76), and decreased to 8 pg/mL (4-28) at 23 months (2-34) after kidney transplantation (p < 0.00005). The maximum concentration of pentagastrin-stimulated CT was 63 pg/mL (25-110) before transplantation and decreased to 20 pg/mL (8-91) (p < 0.00005) thereafter. There was a linear association between CT and calcium as well as between phosphorus and parathyroid hormone at the time of screening. After transplantation, CT correlated with serum creatinine. Therefore, the increase of CT concentration in patients with impaired kidney function presumably reflects 'secondary hypercalcitoninemia' due to C-cell hyperactivity.     

Hypercalcitoninemia in thyroid conditions other than medullary thyroid carcinoma: a comparative analysis of calcium and pentagastrin stimulation of serum calcitonin

Purpose

Calcitonin screening aims at uncovering occult medullary thyroid cancer (MTC) in patients with nodular thyroid disease. Elevated basal calcitonin serum levels call for calcitonin stimulation, the level of which may direct the extent of surgery. Because pentagastrin has become restricted, calcium has increasingly been used instead for stimulation. This study identified a new spectrum of patients demonstrating a false-positive hypercalcitoninemia in the absence of C-cell disease, carrying multinodular goiter (MNG), thyroiditis, and non-MTC thyroid malignancy, and endeavored to explore the feasibility of extrapolating pentagastrin-stimulated to calcium-stimulated calcitonin thresholds.

Methods

Altogether, 43 (9.5 %) of 455 patients with nodular thyroid disease revealed increased basal calcitonin serum levels between 2005 and 2012, for which they underwent intravenous stimulation with pentagastrin (31 patients) or calcium gluconate (12 patients) before and after primary thyroidectomy.

Results

Stimulation with calcium gluconate resulted in significantly higher and more variable preoperative calcitonin serum levels after 2 (241.2 vs. 104.9 pg/mL; P?=?0.018) and 5 min (240.6 vs. 87.4 pg/mL; P?=?0.007) than stimulation with pentagastrin. Stimulation with calcium gluconate produced 10-fold (nodular goiter), 15-fold (thyroiditis), and 21-fold (thyroid neoplasia other than MTC) calcitonin increases over baseline, as opposed to 5-fold, 10-fold, and 8-fold increases after stimulation with pentagastrin. None of the 43 patients, all of whom reverted to undetectable calcitonin serum levels after thyroidectomy, had immunohistochemical evidence of C-cell disease. Subgroup analyses according to gender and thyroid disease, being limited by the low number of patients in each subgroup, did not yield significant differences.

Conclusions

Calcium stimulation yields significantly greater calcitonin levels than pentagastrin stimulation, precluding generalization of pentagastrin-stimulated to calcium-stimulated calcitonin thresholds. After calcium stimulation, false-positive findings appear to be more common in patients of female gender and patients with thyroiditis and thyroid neoplasia other than MTC, potentially effecting surgical overtreatment.     

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.     

Kalzitoninbestimmung zur Frühdiagnose des medullären Schilddrüsenkarzinoms

Calcitonin is considered to be a sensitive marker for medullary thyroid cancer (MTC) therefore early detection and surgical treatment may help to improve the clinical prognosis of MTC. Routine calcitonin measurement has therefore been recommended in the diagnostic evaluation of patients with nodular thyroid disease. In the case of elevated serum calcitonin (>20 pg/ml) stimulation testing is recommended to improve the predictive power for MTC particularly in patients with small nodules. Serum calcitonin measurement cannot reliably discriminate between micro-MTC (<10 mm) and C cell hyperplasia. In patients with stimulated calcitonin levels exceeding 100 pg/ml thyroidectomy is recommended because of a high inherent risk of MTC. Highly elevated basal and stimulated serum calcitonin levels are strongly suggestive of MTC with practical implications for surgical management.     

Surgical treatment of postoperative, incidentally diagnosed small sporadic C-cell carcinomas of the thyroid

BACKGROUND AND AIMS: The surgical strategy in small sporadic C-cell carcinomas of the thyroid that are incidentally diagnosed after goiter resection for benign disease is controversial. It remains unclear whether a completion thyroidectomy should be performed in every case. PATIENTS AND METHODS: We present nine patients who were operated on between October 1992 and October 1997 in whom an unexpected, small sporadic C-cell carcinoma (seven with pT1, two with pT2) was found in the postoperative histology. RESULTS: All patients were calcitonin negative and there were no signs of the disease being inherited (no familial history, negative RET proto-oncogene). No patient underwent a completion thyroidectomy. All patients had a follow-up with pentagastrin-stimulated calcitonin and carcinoembryonic antigen (CEA) 3 months, 6 months and annually after the operation. No patient became calcitonin positive or showed any other signs of tumor recurrence after a follow-up period of 2-7 years. CONCLUSION: A completion thyroidectomy is not necessary in small sporadic C-cell carcinoma that is incidentally diagnosed after resection for benign disease if there is no sign of familial cancer and if calcitonin is negative. A close follow-up is necessary.     

Surgical Strategy in a Kindred with a Rare RET Protooncogene Mutation of Variable Penetrance with Regard to Multiple Endocrine Neoplasia

Prophylactic thyroidectomy is recommended for carriers of RET protooncogene mutations owing to their nearly complete penetrance for medullary thyroid carcinoma (MTC). However, this guideline is challenged by mutations exhibiting variable penetrance of C-cell pathology. A 38-year-old woman presented with pathologic basal and pentagastrin-stimulated calcitonin levels. Genetic analysis revealed a heterozygous RET protooncogene germline mutation in codon 791 (exon 13) (TAT(Tyr)-->TTT(Phe)), followed by thyroidectomy and systematic central lymph node dissection. Histology showed C-cell hyperplasia (CCH) only. Three additional carriers were identified among family members. The 71-year-old father refused surgery despite pathologic calcitonin levels. The index patient's 37-year-old sister had normal basal and stimulated calcitonin levels, and her 6-year-old son had a 10-fold rise of calcitonin after pentagastrin stimulation. Both patients underwent the same operation as the index patient. The sister had 25 hyperplastic C-cells, but the her son had extensive CCH without MTC. The eldest uncle of the index patient had died of metastatic MTC at the age of 52 with unknown carrier status. Despite variable penetrance, each carrier of a RET protooncogene germline mutation should undergo thyroidectomy, even if basal and stimulated calcitonin levels are normal because at present no test can exclude or predict the age of development of MTC. Moreover, pathologic calcitonin levels cannot differentiate between CCH and MTC. Central lymph node dissection is recommended, as lymph node metastases occur early, significantly worsening the prognosis.     

Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated?

BACKGROUND: Mutations of the RET proto-oncogene co-segregate with multiple endocrine neoplasia type 2A. A rare sequence abnormality at codon 804 (c804) has been reported in 6 kindreds and linked to mild C-cell disease, which raises the question of the appropriateness of thyroidectomy in childhood. The purpose of this study was to (1) report the clinical correlates of 5 additional c804 kindreds, and (2) clarify therapeutic options in children. METHODS: Thirty-eight members from five c804 kindreds underwent genetic analysis. Biochemical, operative, and pathology reports were reviewed. RESULTS: Twenty-three gene carriers were identified, of whom 14 had thyroidectomy. Medullary thyroid carcinoma was found in 7 patients (aged 5-56 years), C-cell hyperplasia in 6 patients (aged 13-40 years), and normal histology in a single patient (aged 27 years). One patient with medullary thyroid carcinoma died of metastases (aged 12 years). Nine of the 23 gene carriers delayed operation, 4 of whom had calcitonin testing. Three of the 4 patients had abnormal calcitonin levels and a single patient was negative (aged 40 years). Of the remaining 9 patients, 2 await thyroidectomy, and 3 have refused evaluation. CONCLUSIONS: Penetrance of the c804 mutation is highly variable. Medullary thyroid carcinoma associated with this genotype has aggressive potential. Prophylactic thyroidectomy in childhood is a viable approach.     

Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2

Children with multiple endocrine neoplasia type 2 (MEN2) often develop medullary carcinoma of the thyroid (MCT) or its precursor, C-cell hyperplasia. Survival results are improved if malignancy is diagnosed early from the results of plasma immunoreactive calcitonin (iCT) measurement. The effect of early detection and thyroidectomy in children with MEN2 syndrome was determined by reviewing the experience between 1975 and 1985. Seventeen children with MEN2 who were 12 years old or younger underwent a total thyroidectomy for MCT or C-cell hyperplasia. iCT was measured in all patients preoperatively and postoperatively. Of the 17 children, 14 (82%) had MEN2a and 3 (18%) had MEN2b. There were 14 (82%) female and three (18%) male patients; their mean age was 6.97 years (range 1.5 to 12 years). In all patients, the diagnosis of MCT was made from initial elevated levels of iCT after stimulation with pentagastrin. Three patients had clinical evidence of disease preoperatively. All patients underwent a total thyroidectomy and lymph nodes were removed from the central zone; a neck dissection was performed in the three with clinically obvious disease. MCT with C-cell hyperplasia was found in 11 children and C-cell hyperplasia alone in six. Of the 11 with carcinoma, eight had bilateral disease and three unilateral. Six children had bilateral C-cell hyperplasia. All 17 children were alive and feeling well at the time of this report; however, three had evidence of metastatic disease according to iCT measurements. None of the children had recurrent nerve injuries; one had evidence of hypoparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Isthmus-Preserving Total Bilobectomy: An Adequate Operation for C-Cell Hyperplasia

Background Autopsy studies show that C cells deriving from the ultimobranchial body and migrating into the thyroid do not reach the isthmus region and are distributed along the vertical axes of thyroid lobes. This was confirmed in a surgical series of 58 patients (34 with preoperatively normal and 24 with elevated serum calcitonin) where no calcitonin-positive cells were demonstrable immunohistochemically within separately investigated isthmi. Consequently, isthmus-preserving total bilateral lobectomy (IPTB) may be regarded as an adequate surgical procedure for C-cell hyperplasia (CCH). Patients and Methods IPTB was performed from October 2001 to December 2004 in 64 patients, 59 patients with nodular goiter and slightly to moderately elevated serum calcitonin (stimulated under 500 pg/ml) (group A, apparently sporadic cases) and in 5 patients undergoing prophylactic surgery for hereditary medullary thyroid carcinoma (MTC) with intermediate- or low-risk RET mutations (non-634) (group B). The surgical procedure focused on meticulous total extracapsular resection of both thyroid lobes, preservation of an isthmus remnant of about 3 ml (smaller in children), and histologic workup of the border zones of resection in addition to that of the completely removed lobes. When malignancy could be proven intraoperatively (7 patients) or when the isthmus turned out to contain nodular lesions (4 patients), completion total thyroidectomy (plus lymphadenectomy) was performed as a one-stage procedure. Second-stage total thyroidectomy was performed in 3 cases. Thus, IPTB was the definitive surgical procedure in 50 patients (45 of group A and all 5 of group B). Results In all of the 50 definite IPTB cases, postoperative serum calcitonin was below the measurable limit (2 pg/ml); stimulated calcitonin was below the measurable limit in 47 (including all of group B) and was measurable in 3 sporadic cases in a lower-normal range between 2.4 and 3.5 pg/ml. Genetic screening of the apparently sporadic cases with CCH was positive in one (codon 791). The risk of recurrent laryngeal nerve paralysis seems not to be elevated (0% permanent); permanent hypocalcemia occurred in 1 patient (2%). Follow-up data of 37 patients, median 18 (6–36) months, showed continuously nonmeasurable serum calcitonin with one exception, where it was in the normal range after 18 months. All IPTB patients are still under substitution therapy with L-thyroxine (median 125 μg/day) with decreasing tendency in all 3 children after prophylactic operation, the latter also showing an increasing volume of well-vascularized isthmi (from 1.5 to 2.5 ml). Conclusion IPTB reliably removes all C cells. There may not be need for total thyroidectomy (TTx) in cases with CCH. When necessary, completion TTx can be performed easily without additional risk. IPTB leaves a functionally relevant remnant, corresponding to that of a subtotal resection. This might be of importance especially for prophylactic surgery in children where the isthmus can compensate for the loss of thyroid function with time.     

C-cell hyperplasia of the thyroid in a patient with goitrous hypothyroidism and Hashimoto's thyroiditis

A 63-year-old man with a goiter and primary hypothyroidism due to Hashimoto's thyroiditis was found to have hypercalcitonemia and, though hypothyroid, markedly elevated serum total and free T3 levels. The latter findings were attributable to circulating T3 autoantibodies and interference with radioimmunoassay. An infusion of calcium and pentagastrin resulted in abnormal increases in serum calcitonin levels. Because there was no evidence of a nonthyroidal cause for the hypercalcitonemia, the patient had a total thyroidectomy. Pathological examination of the thyroidectomy specimen revealed typical Hashimoto's thyroiditis and extensive C-cell hyperplasia symmetrically distributed throughout the upper and middle thirds of each lobe. The C cells stained strongly with immunoperoxidase stains for calcitonin, chromogranin, and CEA using absorbed polyclonal anti-CEA antibody. Less extensive staining for CEA was obtained using the monoclonal antibodies for CEA, 374/14, 250/183, and 431/31; only a few reactive cells were noted using 431/31. Postoperatively, serum calcitonin levels fell to normal and did not rise with a repeat calcium-pentagastrin infusion test. This patient appears to be the first instance of C-cell hyperplasia associated with Hashimoto's thyroiditis, while elsewhere an association with medullary thyroid carcinoma has been reported. These observations raise questions regarding a possible pathogenetic relationship between Hashimoto's thyroiditis and C-cell neoplasia.     

Calcitonin gene-related peptide as a tumor marker for medullary thyroid carcinoma.

We have established a radioimmunoassay method for calcitonin gene-related peptide (CGRP) to monitor changes in plasma CGRP levels in patients with medullary thyroid carcinoma (MTC). Preoperative plasma CGRP levels (normal level less than 12.7 pg/ml) were as high as 128 pg/ml to 2,010 pg/ml in all five patients with MTC. Ten of 17 postoperative patients with MTC were positive for CGRP. A provocation test was performed in 12 patients with MTC. Plasma CGRP changes roughly paralleled serum calcitonin levels. In particular, in three patients with poorly-differentiated MTC which progressed aggressively, plasma CGRP levels were increased to 1.4 to 2.0 times levels before the test, i.e., lower than the 2.8- to 23.3-fold increase in nine patients with the well-differentiated MTC. These results suggest that CGRP may be a humoral marker of medullary carcinoma and be related to degree of malignancy.     

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 < or =250 pg/mL. These data could be used to develop a logical, cost-effective treatment and follow-up strategy for patients with MTC.