7B2, a possible marker for nonfunctioning pancreatic islet cell tumor.

Plasma 7B2 was measured in 13 patients with pancreatic islet cell tumors, 11 with pancreatic adenocarcinoma and 31 normal subjects as a control. The mean (+/- SD) concentrations of plasma 7B2 in the normal subjects and the patients with pancreatic islet cell tumors were 67 +/- 10 and 1041 +/- 1786 pmol/l, respectively, and the value in the patients with pancreatic islet cell tumors was significantly higher than that in the normal subjects (p less than 0.01). Elevation of plasma 7B2 over the normal range, defined as less than the mean + 3SD value of those in the normal subjects, was found in 10 of 13 patients with pancreatic islet cell tumors including 4 with nonfunctioning tumor. Plasma 7B2 dropped into the normal range postoperatively in 3 patients with nonfunctioning tumor. Plasma 7B2 concentrations in the patients with pancreatic adenocarcinoma remained in the normal range. These results raise a possibility that 7B2 is a useful marker for pancreatic islet cell tumors, in particular nonfunctioning tumor.     

The ultrastructure of the thyroid medullary carcinoma

The ultrastructure and the morphometrical pattern of secretory granules were studied in six cases of thyroid medullary carcinoma. The tumor cells were fusiform or polyhedral with irregular, mostly elongated nuclei. Phagolysosomes containing a crystalloid material, probably degraded lipoprotein complexes, degeneratively changed mitochondria, moderately developed rough endoplasmic reticulum and Golgi complexes were commonly found. Amyloid occurred as small fibrils in intercellular spaces. Marked dystrophic lesions of tumor cells surrounding amyloid fibrils were found. Numerous roundshaped electron-dense secretory granules were noticed in tumor cell cytoplasms. The morphometrical analysis showed that the size of granules oscillated between 60 and 450 nm with mean values ranging from 171.4 +/- 31.8 to 227.7 +/- 28.1 nm. Frequency distribution curves showed at least two peaks varying with the investigated case at different intervals. In two cases two distinct groups of granules were found within the same cells: one group of electron-dense, compact, smaller sized granules and another group of larger, finely granulated, less dense granules. In the other four cases the granule sizes were more homogeneous. These results might indicate that the granule size depends on the maturation degree and functional activity or that there are several kinds of granules specialized in the secretion of various substances.     

Inheritable forms of medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) arises from parafollicular or C cells of the thyroid that produce calcitonin. It accounts for 5-10% of all thyroid cancers. Hereditary MTC represents 20-30% of all MTCs. It can be transmitted with an autosomal dominant pattern, either as a single entity, familial MTC, or it can arise as part of a multiple endocrine neoplasia (MEN) syndrome type 2A or 2B. The identification of hereditary MTC has been facilitated in recent years by the direct analysis of the ret proto-oncogene.     

Dendritic cell vaccination induces tumor epitope-specific Th1 immune response in medullary thyroid carcinoma.

The existence of inherited aggressive forms of medullary thyroid carcinoma (MTC) and their resistance to classical therapies make it a prime candidate for adoptive immunotherapy. Highly potent antigen-presenting cells, namely dendritic cells (DCs), may serve as an interesting tool for anticancer vaccination. Here we report on the IN VITRO findings of a vaccination trial in five MTC patients, who were treated with a new DC generation protocol consisting of granulocyte-macrophage colony-stimulating factor and interferon-alpha (IFN-DCs). These cells were pulsed with tumor-specific calcitonin and administered twice. In two patients who responded to therapy we found a large increase (in mean 2.9+/-1.9%) of antigen-specific IFN-gamma-secreting CD4+ cells as well as an increase of granzyme B positive CD8+ cells (mean 2.2+/-0.2%) in the peripheral blood. In parallel, a decrease of CD4+/CD25+/FoxP3+ regulatory T cells was seen. Importantly, IN VITRO stimulation of PBMC with 10 different 15mer calcitonin peptides resulted in the identification of two HLA class II epitope regions within the central part of full-length calcitonin. These data were in accordance with the results drawn from the computer-based algorithm epitope prediction software SYFPEITHI. Measurement of different pro- and anti-angiogenic factors did not allow for a distinct outcome of prediction of the treated patients. In summary, we have demonstrated that immunization with IFN-DCs leads to a tumor epitope-specific immune response in MTC patients and may, therefore, represent a promising tool for future vaccination trials.     

Atypical cytologic features of medullary carcinoma of the thyroid. A review of 12 cases.

A total of 12 cases of medullary carcinoma of the thyroid were reviewed with regard to atypical cytologic features. They included clusters of cells with a follicular arrangement, papillary fronds, spindle-shaped cells, pleomorphic nuclei, nucleoli and intranuclear inclusions. Congo red staining on selected destained smears was positive for amyloid in three cases. Histology was also available in 12 cases. Two cases were incorrectly diagnosed as papillary carcinoma and one as follicular carcinoma on cytology. There were no false-positive diagnoses.     

Release of calcitonin by cultures of medullary carcinoma of the thyroid.

Three biopsies of medullary carcinoma of the thyroid were grown in monolayer culture. All three cultures initially released high levels of calcitonin into the medium, but the conretion from the culture cells was not stimulated when the medium calcium concentration was increased from 1.8 to 3.6 mEq/L. Four peaks of calcitonin immunoreactivity were found when the culture medium of one cell line was fractionated by gel filtration on Bio-Gel P-10. This closely corresponded to the heterogeneous molecular profile of calcitonin in the serum of this patient and other patients with medullary carcinoma of the thyroid.     

Familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2B map to the same region of chromosome 10 as multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma (MTC) occurs as a component of three well-described autosomal dominant familial cancer syndromes. Multiple endocrine neoplasia type 2A (MEN 2A) is characterized by MTC, pheochromocytomas, and parathyroid hyperplasia. Patients with the rarer multiple endocrine neoplasia type 2B (MEN 2B) syndrome develop MTC and pheochromocytomas, as well as mucosal neuromas, ganglioneuromatosis of the gastrointestinal tract, and a characteristic "marfanoid" habitus. Finally, MTC is transmitted in an autosomal dominant pattern in some families without associated pheochromocytomas or parathyroid hyperplasia (familial medullary thyroid carcinoma, MTC1(2). Sixty-one members of two well-characterized kindreds segregating MTC1 and 34 [corrected] members of six families segregating MEN2B were genotyped using a panel of RFLP probes from the pericentromeric region of chromosome 10 near a locus for MEN 2A. Statistically significant linkage was observed between the chromosome 10 centromere-specific marker D10Z1 and MTC1 (maximum pairwise lod score 5.88 with 0% recombination) and D10Z1 and MEN2B (maximum pairwise lod score 3.58 with 0% recombination). A maximum multipoint lod score of 4.08 was obtained for MEN2B at the position of D10Z1. In addition, 92 members of a previously unreported large MEN2A kindred were genotyped, and linkage to the pericentromeric region of chromosome 10 is reported (maximum pairwise lod score of 11.33 with 0% recombination between MEN2A and RBP3). These results demonstrate that both a locus for familial MTC and a locus for MEN 2B map to the pericentromeric region of chromosome 10, in the same region as a locus for MEN 2A. The finding that each of these three clinically distinct familial cancer syndromes maps to the same chromosomal region suggests that all are allelic mutations at the same locus or represent a cluster of genes involved in the regulation of neuroendocrine tissue development.     

Metastatic medullary thyroid carcinoma in sputum. A light and electron microscopic study

Medullary thyroid carcinoma (MTC) was diagnosed in a 43-year-old male by light microscopy, electron microscopy and immunohistochemistry. Five years after thyroidectomy, malignant cells with the typical cytologic and electron microscopic features of MTC were seen in his sputum, and extensive pulmonary metastases from MTC were subsequently documented at autopsy. Sputum examination is a useful diagnostic technique in patients with MTC in whom pulmonary metastases are suspected.     

Elevated levels of calcitonin mRNA: a marker for the spontaneous development of medullary thyroid carcinoma in rats

The aging WAG/Rij rats (a Wistar derived strain) develop spontaneously medullary thyroid carcinoma with a high frequency (50%). We have studied calcitonin biosynthesis in Wistar and WAG/Rij rats strains in order to determine if early changes in this parameter occurred in the WAG/Rij strain. Thyroidal and plasma CT levels were measured in three months old WAG/Rij and Wistar rats before and after acute calcium challenge. Total RNA was extracted from thyroid glands and specific CT messenger RNA levels estimated by dot and Northern blot analysis with a 32P-labeled probe specific for CT mRNA. The capacity of mRNA to direct synthesis of CT precursor was also measured by translation in an in vitro system. Though mean basal circulating CT levels were equivalent in both strains, CT release after calcium stimulation was much increased in the WAG/Rij rat. CT content of the glands and CT mRNA levels were two fold higher in the WAG/Rij strain. Thus, in this strain, CT biosynthesis and secretion were increased long before the development of a C-cell carcinoma.     

Specific binding of 1,25-dihydroxycholecalciferol in human medullary thyroid carcinoma.

A specific 1,25-dihydroxycholecalciferol-binding protein has been detected in high-salt cytosols prepared from human medullary thyroid carcinomas. The binding protein had the same equilibrium dissociation constant (Kd = 0.17 +/- 0.05 nM; n = 4) and sedimentation coefficient on sucrose gradients (3.7S) as than seen in established vitamin D target tissues. This protein was not detected in normal thyroid cytosols, which may reflect the low proportion of C-cells within the gland.     

Polyclonal origin of medullary carcinoma of the thyroid in multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC) and other tumors. Since MTC can also occur in a sporadic form and as familial medullary thyroid carcinoma, this neoplasm offers a unique opportunity to investigate the difference of origin, if any, between the sporadic and the hereditary forms of a tumor. While sporadic malignancies have usually been found to result from a mutational event occurring at the single-cell level and are therefore monoclonal, studies on hereditary neoplasms have been scarce and often produced conflicting results. In order to determine the clonal origin of sporadic MTCs and of those occurring in MEN 2 syndromes we used a clonality assay based on a polymorphic trinucleotide repeat of the X-linked human androgen-receptor gene. We found that 10 out of 11 MTCs expressed a polyclonal pattern of X inactivation, including a significant percentage of the cases clinically defined as sporadic. Received: 21 May 1996 / Revised: 14 August 1996     

Physical and radiological findings specific for medullary carcinoma of the thyroid gland.

Preoperative physical and radiological findings, if specific to a certain extent, are important for detecting patients with sporadic form of medullary thyroid carcinoma and especially for the first patient in the family having a hereditary form of medullary thyroid carcinoma and pheochromocytoma syndrome. To delineate clinical features of medullary thyroid carcinoma, a total of 9 patients with this tumor were reviewed retrospectively. In most patients, the thyroid lesions were located in the upper two thirds of the lobe, which was determined by careful palpation or 131I scintiscanning of the thyroid. The primary lesion in the thyroid could be felt more or less as a round, sharply demarcated nodule with fairly good mobility. These findings suggested rather a benign thyroid nodule when there was no lymph node involvement. However, it could be considered a sign suggesting medullary thyroid carcinoma when accompanied by marked lymph node metastasis. In our recent 2 cases, the diagnosis of medullary thyroid carcinoma was strongly suspected on these clinical bases, one of the cases being presented in detail. In 4 patients, lymph node metastasis in the central neck extended to either submandibular or upper mediastinal regions or both. In about one third of the patients, calcified deposits were shown in the cervical roentgenograms. With the use of soft tissue roentgenography, grossly punctate calcific deposits associated with psammoma-like shadows were recognized and the pattern was a criterion for definitive diagnosis of medullary thyroid carcinoma.     

Adrenal-cortical function in patients with medullary carcinoma of the thyroid and pheochromocytoma.

Medullary carcinoma of the thyroid (MCT) is reported to synthesize ACTH. This ACTH is believed to be responsible for the development of Cushing's syndrome in some patients with MCT. To determine the frequency of occurrence of adrenal cortical overactivity in patients with MCT, we measured plasma cortisol concentration and the urinary excretion of 17-hydroxycorticosteroids, 17-ketosteroids and urinary free cortisol in 22 patients with MCT and 7 patients with MCT plus pheochromocytomas. The patients with MCT and MCT plus pheochromocytoma had similar adrenal cortical function to age and sex matched normal subjects. We conclude that adrenal cortical function is usually normal in patients with MCT.