Surgical approach to early familial medullary carcinoma of the thyroid gland

The application of a radioimmunoassay for human calcitonin to a high risk family group has predicted the diagnosis of medullary carcinoma of the thyroid in twelve persons. With the calcium infusion test, elevated levels of calcitonin have been measured in the serum and urine in these patients with medullary carcinoma. In eleven, the tumors were clinically occult.     

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.     

A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease

Purpose

The RET proto-oncogene is involved in neural crest disorders. Activating germline mutations in the RET proto-oncogene cause the development of familial medullary thyroid carcinoma (FMTC) or medullary thyroid carcinoma (MTC) as a part of multiple endocrine neoplasia type 2 (MEN2) syndrome. Inactivating germline mutations in the RET proto-oncogene are detected in Hirschsprung's disease (HSCR). Only in a very small number of families are these 2 diseases expressed together.

Methods

This study presents a novel Czech kindred with FMTC-HSCR phenotype. Two family members (mother and daughter) were tested for RET germline mutations in exons 10, 11, 13, 14, 15, and 16.

Results

Direct fluorescent sequencing of genomic DNA revealed a heterozygous mutation in the RET proto-oncogene in exon 10 at codon C609Y in both persons tested. This family was reclassified, thanks to genetic screening from the apparently sporadic MTC-HSCR to FMTC-HSCR.

Conclusion

The germline mutation was detected because of the systematic genetic screening of the RET proto-oncogene, which is useful for genetic counseling of potential risk of HSCR and MTC in other family members. This family could be added to the small worldwide cohort of families with MEN2A/FMTC-HSCR.     

Nonfamilial medullary thyroid carcinoma

On the basis of this report and the current literature, we conclude that the familial type of medullary thyroid carcinoma can be diagnosed early using basal and poststimulation levels of calcitonin. However, most of the patients with sporadic disease present with a neck mass later in life. The tumor has a tendency to invade locally and metastasize to lymph nodes early in its course. Prognosis is negatively influenced by the extent of disease, lymph node involvement and elderly age. The surgical procedures of choice should be total thyroidectomy with clearance of central nodes of the neck as well as neck dissection when indicated. All parathyroid glands should be inspected. For patients treated for cure, the determinant 10 year survival is 48 percent, and 20 year survival is 33 percent. Recurrence of local disease should be treated aggressively, as important palliation and prolongation of life can be achieved. Radiotherapy may be helpful in the management of residual tumor or recurrent disease. Basal calcitonin assays and poststimulation studies are useful in diagnosing residual or recurrent disease. In the familial cases, the existence of other endocrinopathies has to be considered in the management of the patients.     

Presurgical assessment of the tumor burden of familial medullary thyroid carcinoma by calcitonin testing

BACKGROUND: Early diagnosis of familial medullary thyroid carcinoma (MTC) is currently done by genetic analysis. These techniques have replaced calcitonin stimulation testing, which was previously used for this purpose. Some studies suggest a relationship between MTC spread and calcitonin levels. The aim of this study was to assess whether the tumor burden of MTC associated with multiple endocrine neoplasia type 2A (MEN 2A) syndrome can be estimated from the plasma calcitonin values before surgery. STUDY DESIGN: We retrospectively studied the relationship of basal and peak calcitonin values before thyroidectomy with histopathologic findings in 53 patients with MEN 2A syndrome from 14 families. The MTC was classified according to TNM staging. Analysis of variance was used for statistical analysis complemented with equality contrasts for pairs of means by the least significant difference method with a Student's t-test and with the Bonferroni's adjustment. RESULTS: A positive association was found between tumor stage and basal and peak calcitonin levels. There were significant differences between the following: mean basal concentrations of patients with C cell hyperplasia (CCH) (34.3 pg/mL) and TNM stage II (1,097.4 pg/mL), p < 0.01; CCH and TNM stage III (2,940.8 pg/mL), p < 0.001; TNM stage I (165.3 pg/mL) and stage II (1,097.4 pg/mL), p < 0.01, and between TNM stages I and III, p < 0.001. Poststimulation mean concentrations were different between CCH (48.7 pg/mL) and TNM I (514.2 pg/mL), p < 0.001. CONCLUSIONS: Preoperative calcitonin testing may be useful for assessing tumor spread and should be considered when deciding the extent of surgery for MEN 2A MTC.     

Calcitonin, calcitonin gene-related peptide, and gastrin-releasing peptide in familial thyroid medullary carcinoma

We examined immunocytochemically the occurrence of the three peptides calcitonin, calcitonin gene-related peptide (CGRP), and gastrin-releasing peptide (GRP) in medullary carcinoma of the thyroid. We also sought to determine whether the plasma levels of these peptides were increased when stimulated with calcium and pentagastrin in familial medullary carcinoma of the thyroid (MCT). The tumor tissue from all 17 cases examined was found to exhibit calcitonin and CGRP immunoreactivity, and in 15 of the 17 cases the tumor tissue also contained GRP immunoreactivity. In 7 of the cases selected at random, an intravenous injection of calcium carbonate (2 mg/kg body weight) and pentagastrin (0.6 microgram/kg body weight) produced marked elevation in plasma levels of calcitonin but did not significantly alter the plasma levels of CGRP or GRP. We conclude that most MCT tumors contain CGRP and GRP immunoreactive cells but that the plasma levels of CGRP and GRP are not altered on stimulation. This finding is clearly in contrast to the markedly elevated calcitonin levels. Hence, determination of plasma calcitonin levels still seems to be the most appropriate diagnostic test for MCT.     

Hormone-dependent medullary carcinoma of the thyroid

An unusual case of complete regression of pulmonary metastases of medullary carcinoma of the thyroid after oral administration of thyroid extract is presented. The patient has remained free of disease for three and a half years. This treatment has few side effects and may be as effective as is the administration of radioactive iodine or external radiation. For these reasons, it should be tried despite adverse pathologic indications.     

Surgical therapy of medullary thyroid carcinoma

This study describes the findings of a retrospective study of 57 medullary thyroid cancer patients observed at the main Sicilian centres for endocrine surgery. Six of these patients were observed locally in order to add a further dimension to the discussion of surgical therapies for medullary thyroid carcinoma. A review of the literature on sporadic forms of medullary thyroid carcinoma and hereditary neoplastic syndromes is followed by presentation of the authors' series. Diagnostic protocols, surgical therapies and pathological observations are discussed. Particular attention is paid to patterns of metastases of medullary thyroid carcinoma and to the differing opinions regarding the extent of lymph-node dissection required and the treatment of recurrent disease. Total extracapsular thyroidectomy with lymph-node dissection is identified as the gold standard of surgical therapies for this form of cancer.     

Immuno-histochemical study of medullary thyroid carcinoma

Five peptide hormones including calcitonin (CT) and gastrin-releasing peptide (GRP), serotonin (5HT), CEA, nervous tissue specific proteins and monoclonal antibody Leu-7 were immuno-histochemically studied on 60 cases of medullary thyroid carcinoma (MTC). In addition, localization of varied products in the tumor cells and its relations with the clinical features in some cases were evaluated. MTC contains a variety of products in many cases, and CT and CEA were positive in all cases. In 50 of the 57 cases (87.7%), GRP was positive, which suggested that GRP could be a novel tumor marker for this tumor. Furthermore, in tumor cells and C-cell hyperplastic foci, identical cells were sometimes revealed to possess both CT and GRP. Existence of somatostatin (SS), substance-P (SP), beta-MSH, 5 HT, Leu-7 and NSE in the tumor cells were confirmed. NSE was positive in 32 of the 47 cases (61.8%) which could confirm that MTC possesses neuroendocrine nature. In two cases of autopsy in which the tumors were highly malignant in clinical course and undifferentiated in histology, most tumor cells showed poor stainability for peptide hormones, suggesting that specific qualities as neuroendocrine tumor had been lost. In familial cases, the tumor tended to contain multiple substances.     

Surgical management of medullary thyroid carcinoma

Medullary thyroid cancer (MTC) is a malignant tumor of the parafollicular C cells of the thyroid and comprises only 1–2% of all thyroid cancer cases. Unlike most differentiated thyroid cancer, MTC is associated with a mean survival of 8.6 years and accounts for a disproportionate 8.6% of thyroid cancer deaths. Surgery is the mainstay of treatment for loco-regional disease and the only current means of cure for MTC. The relatively low incidence of MTC has made the comprehensive study of this disease difficult and most research to date has been based largely on single institution, retrospective, and/or non-randomized studies. Despite various professional organizations such as the American Thyroid Association establishing guidelines for the diagnosis and treatment of patients with MTC, there is still significant variation in actual practice patterns with regard to the extent of surgery, as well as the management of persistent or recurrent disease. The purpose of this review is to discuss the latest updates in the surgical treatment of MTC, as well as the management of locally advanced, recurrent, and metastatic disease based on the most recent data and expert consensus guidelines.     

Management of medullary carcinoma of the thyroid

Total thyroidectomy is universally advised for the familial variety of MCT. Although total thyroidectomy is also recommended for sporadic cases, partial thyroidectomy may be adequate. Cervical and upper mediastinal nodes should be sampled for microscopic study, even when they are small and appear to be normal. Appropriate neck or mediastinal nodes should be sampled for microscopic study, even when they are small and appear to be normal. Appropriate neck or mediastinal dissection is done if metastasis is present. External radiation is a valuable adjuvant to surgical excision following the apparent complete resection of the tumor, and is beneficial in the management of unresectable disease. Despite local control, patients continue to die from disseminated disease; therefore, there must be a continued search for an effective chemotherapeutic program. Much remains to be learned from calcitonin monitoring of MCT patients.     

Prognostic significance of nondiploid DNA determined by flow cytometry in sporadic and familial medullary thyroid carcinoma

To clarify the role of DNA measurements in predicting outcome after surgical treatment of medullary thyroid carcinoma (MTC), we performed flow cytometric analysis in nuclear suspensions of 119 MTC tumors. Of the 119 patients, 63 (53%) patients had sporadic tumors and 56 (47%) patients had familial tumors; survivors were followed for a mean of 13 years. DNA content was normal in 92 (77%) patients and abnormal (nondiploid) in 27 (23%) patients. Ten-year cause-specific mortality rates were 12%, 42%, and 49% with diploid, tetraploid/polyploid, or aneuploid tumors (p = 0.0009) and were greater with nondiploid tumors both in the sporadic (p = 0.012) and multiple endocrine neoplasia (familial) cases (p = 0.114). None of 27 patients with TNM stage I disease died of MTC. In patients with TNM stages II, III, and IV disease, DNA nondiploid tumors were associated with increased deaths from MTC. In a Cox proportional hazards model involving all 119 patients and adjusted for disease stage and inheritance pattern, nondiploid DNA was independently associated with increased deaths from MTC (p = 0.008). In an identical Cox model restricted to the 92 DNA diploid tumors, an S-phase fraction of 15.0% or more remained a significant variable (p = 0.034) after adjustment for stage and inheritance pattern. We therefore conclude that DNA measurements do have a role to play in predicting outcome after surgical treatment of MTC.