Failure of medullary carcinoma of the thyroid to respond to doxorubicin therapy

We describe 3 patients with metastatic medullary carcinoma of the thyroid who were treated with doxorubicin hydrochloride (Adriamycin). Serum calcitonin was measured before and after doxorubicin therapy. Doxorubicin failed to arrest the progression of the disease in any of the patients. Although serum calcitonin levels dropped in 1 patient during therapy, they remained markedly elevated in all 3 patients. From the present series it appears that medullary thyroid carcinoma often does not have a response to doxorubicin.     

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.     

Melanin-producing medullary thyroid carcinoma with glandular differentiation

A rare case is reported of melanin-producing medullary thyroid carcinoma in a 62-year-old man. Intraoperative imprints of the thyroid tumor revealed numerous detached tumor cells containing large amounts of brown pigment. The Fontana-Masson argentaffin reaction with bleach confirmed that those granules were melanin. Histologically, the tumor was composed of two different components--a medullary area with hyalinized stroma and a follicular area. Melanin was scattered in both areas. The tumor cells in both areas were immunoreactive to carcinoembryonic antigen, calcitonin, gastrin-releasing peptide, somatostatin, met.-enkephalin, neuron-specific enolase, chromogranin and neurofilaments, and negative for thyroglobulin and S-100 protein. The histologic diagnosis was melanin-producing medullary thyroid carcinoma with glandular differentiation. Although various kinds of peptides and amines have been reported to be produced in medullary thyroid carcinoma, melanin production is quite rare; this appears to be only the third reported case.     

De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma

Doxorubicin and camptothecin are two cytotoxic chemotherapeutic agents triggering apoptosis in various cancer cells, including thyroid carcinoma cells. Recent studies revealed a critical role of ceramide in chemotherapy and suggested that anti-cancer drugs may kill tumor cells through sphingomyelinase activation. However, in comparison to sphingomyelin hydrolysis, the relative involvement of de novo ceramide synthesis remained poorly explored and highly controversial. Here, we evidenced that both doxorubicin and camptothecin triggered ceramide accumulation in thyroid carcinoma cells. We demonstrated that ceramide increase occurred via the de novo pathway without neither acidic nor neutral sphingomyelinase contribution. Interestingly, de novo ceramide generation was responsible for the drug-induced malignant cell apoptosis through a caspase-3-dependent pathway and a decrease of thrombospondin amount. Furthermore, blocking ceramide metabolism by inhibiting glucosylceramide synthase strengthened the camptothecin and doxorubicin-dependent effects. Altogether, we evidenced that de novo ceramide synthesis mediates the anti-tumor properties of doxorubicin and camptothecin in thyroid carcinoma and suggested that glucosylation of ceramide may contribute to the drug-resistance phenotype in thyroid malignancies.     

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.     

Oncogene expression in a medullary thyroid carcinoma

We report the expression of Ha-ras, fos, c-myc and N-myc mRNA in a human medullary carcinoma of the thyroid gland, both in primary tumor and lymph node metastasis, as demonstrated by in situ hybridization and Northern blot analysis. A significant difference in the oncogene expression in the primary tumor and the metastasis was not observed. Tumor tissue revealed a significant overexpression of Ha-ras, c-myc and N-myc mRNA as compared to the normal thyroid gland. The amount of fos mRNA expression in non tumorous thyroid gland did not significantly differ from tumor tissue, sis, fms and abl mRNA expression was not detectable in tumor tissue and non tumorous thyroid gland. We conclude, that the (over)expression of the oncogenes Ha-ras, c-myc and N-myc may be associated with initiation and progression of medullary thyroid carcinoma. Similar studies on additional cases of human medullary thyroid carcinoma will be necessary to reveal further information.     

Pituitary metastasis of follicular thyroid carcinoma

OBJECTIVE: The case of a 60-year-old male patient with follicular thyroid cancer who developed a pituitary mass proved to be a metastasis from thyroid cancer. METHODS: Assessment with whole-body scan, ultrasound, computed tomography and thyroglobulin measurements. RESULTS: Despite surgery and repeated doses of radioiodine, the patient developed diplopia and ptosis of the right eyelid, along with increasing thyroglobulin levels. A pituitary mass was discovered, with no signs of pituitary deficiency. The mass was removed and found to consist of neoplastic cells immunohistochemically positive to thyroglobulin. CONCLUSIONS: Distant metastases may develop in cases of follicular thyroid carcinoma, even after repeated doses of (131)I. Metastatic follicular thyroid carcinoma to the pituitary is a rare entity.     

Ultrastructural pathology of the thyroid folliculo-papillary and follicular carcinoma

Twenty cases of thyroid carcinoma (10 follicular and 10 folliculo-papillary) were ultrastructurally studied. In the follicular carcinoma the most striking features were: microfollicular cavities with microvilli from the apical surface of the tumorous cells, intracellular microlumens, swollen mitochondria sometimes containing electrondense bodies and tightly packed filaments. In the solid sheaths light and dark cells were present. Golgi complexes were disposed in small dense cristae. The nuclei were large, round, oval or with a folded appearance. In the folliculo-papillary carcinoma were found nuclei with an irregular shape containing stage I and stage II inclusions, dilated endoplasmic sacks, closely packed, sometimes dystrophic mitochondria, dense bodies or tightly packed parallel filaments and numerous phagolysosomes. The peroxidase activity wa present as black precipitates in the nuclear envelope or around colloid droplets. The acid phosphatase activity was found as unhomogeneous precipitates inside the lysosomes. From this study it could be concluded that the follicular and folliculo-papillary carcinomas have some common ultrastructural features; the ultrastructural and cytoenzymological patterns suggest marked alteration of the synthesis, storage and secretion of thyroid hormones.     

Calcium infusion and pentagastrin injection in diagnosis of medullary thyroid carcinoma.

Calcium infusion and pentagastrin injection were compared as tests to stimulate calcitonin secretion for the detection of medullary carcinoma of the thyroid. Plasma concentrations of immunoreactive calcitonin were measured by radioimmunoassay before and during both stimulation tests in 2 persons who had been found at operation to have medullary thyroid carcinoma, 1 relative in whom a cervical lymph node biopsy had shown medullary thyroid carcinoma and 36 asymptomatic relatives. The tests were carried out on separate days by intravenous infusion of calcium gluconate for 2 hours, to provide 3.75 mg/kg of elemental calcium per hour, and rapid intravenous injection of 0.5 microgram/kg of pentagastrin. Before stimulation immunoreactive calcitonin was undetectable in the plasma of 34 of the 36 asymptomatic persons; the 2 with elevated baseline concentrations of the hormone had a positive response to both tests. Seven others showed an increase in plasma immunoreactive calcitonin concentration only after pentagastrin injection. The two persons with initially elevated values and three of the seven with increased values after pentagastrin injection were found at subsequent operation to have focal medullary carcinoma and parafollicular cell hyperplasia; after the operation immunoreactive calcitonin was undetectable in the plasma, even after stimulation. Rapid injection of pentagastrin is more reliable than slow infusion of calcium as a stimulation test for the early detection of medullary thyroid carcinoma.     

MIB-1 immunohistometry of follicular adenoma and follicular carcinoma of the thyroid gland

OBJECTIVE: To analyze cellular proliferative activity, MIB-1 immunopositivity of normal tissue (n = 20), follicular adenoma (n = 30) and follicular carcinoma (n = 32) of the thyroid gland was analyzed by means of immunohistometry. STUDY DESIGN: Immunohistochemical reactions were performed on 3-micron sections from routinely formalin fixed and paraffin embedded surgical specimens using an indirect peroxidase method. The rate of immunostained cells was determined using the CM-2 TV image analysis system (Hund, Wetzlar, Federal Republic of Germany). Forty viewing fields (1.94 mm2) were measured with 20:1 objective magnification. An average of 5,965 cells were assessed in each case. RESULTS: Mean MIB-1 immunopositivity was higher in follicular carcinoma (average, 2.30%) and follicular adenoma (0.58%) than in normal thyroid tissue (0.14%). The distribution of single values differed significantly between groups (P < .001). To test the suitability of MIB-1 immunohistometry for the differential diagnosis of follicular adenoma and follicular carcinoma, different four-field tables with varying thresholds were calculated. Using a threshold of 0.9%, follicular carcinoma could be detected with a sensitivity of 75% (24/32) and a specificity of 83% (25/30). If a specificity of 90% is required (27/30), the sensitivity of the test decreases to 69% (22/32), based on a threshold of 1.1%. CONCLUSION: As some overlap of single values has to be considered, MIB-1 immunohistometry, although presenting new insights into the proliferative potential of thyroid lesions, is of only limited value for the differential diagnosis of follicular lesions in routine surgical pathology.     

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.