Ultrastructural demonstration of calcitonin in osmium-fixed human medullary carcinoma of thyroid by the protein A-colloidal gold technique

Summary In two medullary carcinomas of the thyroid gland two types of secretory granules were found electron microscopically in the cytoplasm of the tumour cells. The sizes of the granules in one case ranged 103–345 nm in diameter; they were round in shape, and they co-existed in the same tumour cell. They could not, therefore, be distinctively subdivided into two types. In another case, secretory granules in the cytoplasm closely resemble EC granule in morphology. Using the protein A-colloidal gold (PAG) technique the content of secretory granules could be identified as calcitonin irrespective of their sizes or morphology. Immunoreactivity at the ultrastructural level was fairly well preserved even in the osmium-fixed tumour cells. The labelling index, expressed as a mean number of gold particles per unit square area of the secretory granule, was higher in the non-osmium-fixed tumour cells than in the osmium-fixed. Non-osmium-fixed tumour cells embedded either in epoxy or methacryl resin were almost equally labelled with gold particles. The result indicates that the PAG method is practicable to demonstrate the ultrastructural localization of calcitonin even in the osmium-fixed, epoxy resin embedded material.     

Solid cell nests of the thyroid in medullary thyroid carcinoma

Solid cell nests of the thyroid gland were studied in 44 patients with medullary thyroid carcinoma. In 10 (22.7%) patients, solid cell nests were revealed in the vicinity of tumour foci (five cases) or in the contralateral thyroid lobe and isthmus (four cases); in one case the location was indeterminate. In all seven cases in which immunohistochemical studies were carried out, solid cell nests showed negative staining for thyroglobulin, calcitonin and chromogranin A, findings which were distinct from those in medullary thyroid carcinoma. It is therefore suggested that solid cell nests of the thyroid are not precursors of this tumour.     

Melanin production in medullary thyroid carcinoma

A case of melanin-producing medullary thyroid carcinoma is reported in a 51-year-old man. Histologically, the tumour had a typical pattern of medullary thyroid carcinoma with numerous scattered pigmented cells which contained large amounts of melanin pigment as confirmed by bleached Fontana-Masson stain. Immunohistochemical staining revealed positivity of almost all tumour cells for calcitonin and chromogranin, whereas S-100 protein and HMB-45 staining was positive only in the pigmented tumour cells. This finding confirms the ability of medullary thyroid carcinoma cells to have multidirectional differentiation, although melanocytic differenciation remains an exceptional phenomenon.     

The endocrine component of prostatic carcinomas, mixed adenocarcinoma-carcinoid tumours and non-tumour prostate. Histochemical and ultrastructural identification of the endocrine cells

Two types of endocrine-paracrine (EP) cells have been detected histochemically and ultrastructurally in normal and hyperplastic prostates; i.e. type I cells resembling intestinal EC (enterochromaffin) cells and type 2 cells similar to urethral EP cells previously reported by Casanova et al. (1974). About one-third of the 40 prostatic carcinomas studied contained EP cells: two of these were composite tumours exhibiting both adenocarcinomatous and carcinoid patterns. These four tumours have also been studied histochemically and ultrastructurally. ACTH and beta-endorphin immunoreactive cells, ultrastructurally resembling pituitary corticotrophic cells, have been identified in three tumours. Cells identical with type I and type 2 cells of the normal prostate were detected in two cases and in a further case, respectively.     

Metastasizing neuroendocrine carcinoma of the larynx with calcitonin and somatostatin secretion and CEA production,resembling medullary thyroid carcinoma

Summary A 55-year-old man presented with a metastasizing moderately differentiated neuroendocrine carcinoma of the larynx (atypical carcinoid). Immunocytochemical demonstration of neuroendocrine markers (neuron-specific enolase and chromogranin-A) and presence of membrane-bound neurosecretory granules in the cells established the neuroendocrine nature of the tumour. In addition, the tumour was found to produce calcitonin, somatostatin and carcino-embryonic antigen (CEA). Calcitonin and somatostatin were also secreted. On the basis of this particular marker constellation the tumour closely resembles medullary thyroid carcinoma. Review of the recent literature on carcinoids of the larynx reveals immunoreactivity for calcitonin and CEA in a high percentage of cases.     

Melanin production in black medullary thyroid carcinoma (MTC)

Melanin production by two medullary carcinomas of the thyroid is reported and discussed. In both tumours, melanin and calcitonin could be detected in the same cells.     

Mucosubstances in medullary carcinoma of the thyroid

We have studied mucosubstances in 12 cases of medullary carcinoma of the thyroid using histochemical techniques and a number of different lectins. Immunohistochemical staining for calcitonin and carcinoembryonic antigen was also performed. We have found that the presence of mucosubstances is a constant finding in medullary carcinomas; they were present extracellularly in 100% of cases and intracellularly in 53.3%. In both these compartments there was a predominance of neutral over acid mucosubstances. Receptors for UEA-I, Con A, RCA-I, Succ-WGA and SBA were found in many cells in the majority of cases, but there were differences in the affinity from one case to another. Because of this lack of specificity lectin histochemistry is not of diagnostic value in medullary carcinomas of the thyroid. The possible relationships of the lectin-binding results to glycosylated hormone precursors and carcinoembryonic antigen are discussed.     

Medullary thyroid carcinoma and multiple endocrine neoplasia type 2

Medullary thyroid carcinoma (MTC) occurs as both a sporadic and an inherited disease. MTC is a consistent feature of multiple endocrine neoplasia (MEN) 2A, MEN 2B, and familial non-MEN MTC (FMTC). Plasma calcitonin is a sensitive and specific marker for the presence of MTC. Genetic testing can identify mutant gene carriers, and prophylactic total thyroidectomy should be carried out in patients with the mutant gene. The outcome of MTC is progressively worse in FMTC, MEN 2A, sporadic MTC, and MEN 2B, and MEN 2B has been found to have the worst prognosis. There is a significant genotype-phenotype correlation, which allows a more sensitive individualized approach to the timing and extent of prophylactic thyroidectomy.     

Composite metastatic carcinoma in lymph nodes of patients with concurrent medullary and papillary thyroid carcinoma: A report of two cases

Synchronous occurrence of medullary and papillary carcinoma of the thyroid gland is very rare. We describe two cases of synchronous medullary and papillary carcinoma of the thyroid. In both cases, medullary carcinoma and papillary carcinoma were separate in the thyroid but mixed in some of the lymph node metastases. A review of the literature and our own cases revealed that composite medullary and papillary carcinoma metastases in the lymph nodes is a common feature of patients with synchronous medullary and papillary carcinoma of the thyroid gland.     

Ultrastructural and electron immunohistochemical features of medullary thyroid carcinoma

Summary An ultrastructural study, both morphological and immunohistochemical, has been carried out on eight thyroglobulin-positive and nine thyroglobulin-negative medullary carcinomas of the thyroid. The morphometric analysis of granule size showed that all tumours contained cells with small granules and cells with medium size granules, whereas eight tumours had additional cells with large granules. The small granules had an electron dense core, while the medium and large sized granules were both pale-cored and dense-cored. The cells with small, medium or large secretory granules were all immunoreactive for calcitonin and CGRP. No ultrastructural differences were observed between thyroglobulin-positive and thyroglobulin-negative cases of medullary carcinoma of the thyroid.     

Light-electron microscopic and cytochemical studies on the morphogenesis of familial medullary thyroid carcinoma

Summary Six cases of familial medullary thyroid carcinoma (MTC) were investigated by light and electron microscopy as well as by ultracytochemical methods. Light microscopic examination revealed multifocal C-cell proliferation in 5 subjects. These cells were mostly limited to thyroid follicles, but occasionally extended across the follicular capsule forming microscopic MTC. Electron microscopic examination showed that, in some follicles, the proliferating C-cells were still covered by a continuous layer of follicular cells, whereas in others the proliferation extended to the follicular center. C-cells were in direct contact with the colloid, and ultramicroinvasion of the follicular capsule was detected. These observations are consistent with the hypothesis that familial MTC seems to begin as multifocal C-cell proliferation, limited at first to thyroid follicles, between the capsule and the follicular epithelium. Later, the proliferation extends to the follicular center, and C-cells come in contact with the colloid, at which time an in situ carcinoma stage is reached. Some neoplastic cells invade the follicular capsule and, finally, multiple MTC appear and eventually conglomerate.Generally, there were no constant morphologic criteria for a dysplasia or neoplasia among the proliferating C-cells limited to thyroid follicles, when compared with normal or even malignant C-cells. For these reasons, a hyperplastic or dysplastic process preceding MTC cannot be clearly distinguished from a neoplastic process. Our study, however, shows that a light microscopic, apparently hyperplastic process may be a malignant one.Amyloid was present in the more voluminous MTC, associated with tumor cell necrosis, but it was not evident in small MTC and within the foci of C-cell proliferation.Ultracytochemical techniques revealed that the secretory granules of normal, proliferating and neoplastic C-cells contained polysaccharides and/or glycoproteins.This investigation was supported by the MacDonald-Stewart Foundation of Montreal, and the Medical Research Council of Canada     

Calcitonin secretion,C cell differentiation and proliferation during the spontaneous development of murine medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC), a C cell neoplasm, synthesizes large amounts of calcitonin (CT), its biological marker. However, in some cases with a poor prognosis, MTC is associated with low basal CT levels owing to a decrease in the thyroid CT content. Using a murine model of human MTC, we studied the relationships between CT biosynthesis, C cell proliferation, and the circulating CT level during MTC progression. Cell proliferation was revealed by autoradiography of radioactive thymidine incorporation in dividing nuclei, after CT or CT mRNA detection by immunocytochemistry (ICC) or in situ hybridization (ISH). All rat thyroids showed a severe hyperplasia of C cells containing significant amounts of CT and CT mRNA, and a very low mitotic index. Tumours were found in 68% of the thyroids. In the strongly immunoreactive small nodules (ICC+), many labelled nuclei were observed. Subsequently some nodular cells, still containing detectable CT mRNA (ISH+), were not detected by immunocytochemistry (ICC-) owing to a dramatic decrease in secretory granules. Their mitotic index increased, and a rise of the basal CT plasma level was noted. These ISH+, ICC- tumour MTC cells represent a modified aggressive tumour C cell population exhibiting an increased ability to proliferate and were detected by the rise in the basal circulating CT level.This work was supported by grant no. 6424 from the Association pour la Recherche sur le Cancer to F. Treilhou-Lahille     

Ultrastructural study of poorly differentiated medullary carcinoma of the thyroid

Summary Five cases of sporadic medullary carcinoma of the thyroid (MTC) with rapidly progressive disease were studied ultrastructurally. The tumour cells had poorly differentiated C cell characteristics. They exhibited smaller secretory granules in their narrow cytoplasm. Morphometric analysis disclosed that the average diameter of the secretory granules of the cases with a poor prognosis was 173.0 nm in comparison with 254.2 nm of well differentiated cases. The granules were fewer in the poor prognostic group (1.31/µ²) than the well differentiated group (2.75/µ²). Increased free ribosomes and polysomes were noted in the cytoplasm and dispersed chromatin in the nuclei. These cases should be therefore classified as poorly differentiated MTC rather than atypical or anaplastic MTC.     

遗传性甲状腺髓样癌的诊断及治疗

目的探讨遗传性甲状腺髓样癌的诊断及诊疗，为其早期诊断及正确治疗提供依据。方法总结遗传性性甲状腺髓样癌患者的临床资料，对其病因、早期诊断及治疗等方面进行探讨。结果遗传性性甲状腺髓样癌是一种由RET原癌基因的种系突变引起的常染色体显性综合征。发病通常是多病灶性和双侧性的，并且大部分（95％）都发生在年轻人；合理的手术治疗可以取得满意的疗效。结论遗传性性甲状腺髓样癌是一种遗传性疾病，早期诊断、合理的手术治疗治疗可以取得满意的疗效。患者家族成员应长期随访。     

Mixed medullary and follicular carcinoma of the thyroid

Summary We report a case of medullary carcinoma of the thyroid which on light microscopy showed not only the well known arrangement of cells in sheets and nests but also unequivocal follicular structures. These follicular structures are present both in the primary tumor and in lymph node metastases. Immunohistochemical investigations revealed that the cells lining the follicles produce thyroglobulin, whereas the remaining tumor tissue is positive for calcitonin and carcinoembrionic antigen. This case represents a medullary carcinoma of the thyroid with an atypical pattern consisting of both thyroglobulin and calcitonin producing cells.Dedicated to Prof. K. Akazaki, Nagoya/Japan, on the occasion of his 80th birthday