Multiple endocrine cell types in thyroid medullary carcinoma

Summary 10 cases of thyroid medullary carcinoma (TMC) have been studied ultrastructurally and histochemically. Well differentiated calcitonin-producing C cells were present in all tumours, being prevalent in 9 cases. 5-Hydroxytryptamine (5HT) storing cells were found in two cases, somatostatin immunoreactive cells in at least 5 cases and ACTH-immunoreactive cells in 4 cases. Ultrastructurally, at least 3 types of apparently non-C cells were observed. Type 1 cells with large, poorly osmiophilic granules resembling those of gastroenteropancreatic D cells, were present in 6 cases; they appeared to correlate well with somatostatin immunoreactive cells. Type 2 cells with large osmiophilic granules were found in 5 cases; they resembled ACTH-MSH cells of the human pituitary and may correspond to the ACTH-immunoreactive cells of light microscopy. Type 3 cells with small granules and an unknown function were found in 6 cases, always in scarce number. It is concluded that TMC, although mainly made up of C cells, usually contains large proportions of other endocrine cell types.Supported in part by grant N. 75.00630.04 from the Italian National Research Council (C.N.R.). P.F. is a fellow of the Fondazione Anna Villa Rusconi, Varese     

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.     

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.     

Detection of calcitonin and calcitonin gene-related peptide mRNA in human medullary thyroid carcinoma. A retrospective study

In Situ hybridization finds many applications in modern pathology. In many cases, special attention is paid to the processing of the tissues prior to in situ hybridization. In order to investigate the value of RNA in situ hybridization (RISH) in retrospective studies, we performed RISH for calcitonin and calcitonin gene-related peptide (CGRP)-I and HomRNA in eight medullary thyroid carcinomas processed in 1981–1983. RISH was successful with radioactive calcitonin and CGRP-1 probes. With biotinylated probes, only calcitcnin-specific probes gave adequate results. The concentrations of CGRP mRNA were probably too low to be detected by non-radioactive RISH. The results of RISH were correlated with the immunohistochemical localization of the polypeptides. The results matched in all cases except one, where hybridization for calcitonin mRNA was found, but no immunoreactive calcitonin polypeptide. We con-clude that RISH can be successfully used for retrospective analysis, even after long storage of tissue embedded in poraffin.     

Demonstration of calcitonin and carcinoembryonic antigen (CEA) in medullary carcinoma of the thyroid (MCT) by immunoperoxidase technique

The presence of calcitonin and of carcinoembryonic antigen (CEA) was studied in six cases of medullary carcinoma of the thyroid using an immunoperoxidase technique. In five cases the material was obtained surgically and in one at autopsy. Tissue from primary tumours as well as from metastases was studied. Calcitonin and CEA were identified within all the tumours studied, although their pattern of distribution and staining intensity varied both within the cells and within the tumour. Some parts of the tumour contained both CEA and calcitonin, while others stained positively only for one of these substances. In some parts of the tumour there was no positive staining for either substance. Within the cells, CEA showed a typical linear distribution along cell surfaces, while calcitonin showed a more even cytoplasmic distribution and the deposits were more granular. Normal tissue surrounding tumour deposits did not show positive staining. It is considered that cells of medullary carcinoma of the thyroid contain both calcitonin and CEA. Identification of CEA and calcitonin in tumour tissue can be used as a diagnostic aid to identify medullary carcinoma of the thyroid. Iit is considered that these substances are being produced by this tumour and can be used as tumour markers.     

Role of voltage-dependent calcium channels in secretion of calcitonin from human medullary thyroid carcinoma cells

Summary Extracellular calcium concentration is an important regulator of calcitonin secretion. We used primary cell cultures of human medullary thyroid carcinoma to study the role of voltage dependent calcium channels for stimulus secretion coupling. Increasing extracellular calcium concentration (1.6–5.0 mM) in the medium caused a dose dependent release of calcitonin. The calcium channel activator BAY K 8644, a dihydropyridine, stimulated calcitonin secretion in a dose dependent manner (10^–7–10^–5 M). This effect was completely inhibited by equimolar concentrations of the calcium channel blocker nifedipine and abolished in the absence of extracellular calcium. Similarly, nifedipine suppressed the stimulatory action of extracellular calcium. The effects of calcium and BAY K 8644 with and without nifedipine suggest that calcium influx via voltage dependent calcium channels plays an important role in calcitonin secretion. The primary cell culture of human medullary thyroid carcinoma is a good model for the study of stimulus secretion coupling.Abbreviations CT calcitonin - [Ca²⁺]_e extracellular calcium concentration - [Ca²⁺]_i intracellular calcium concentration=cytosolic free calcium concentration - MTC medullary thyroid carcinoma Supported by Deutsche Forschungsgemeinschaft, grant Raue 327/1–2 and Tumorzentrum Heidelberg/Mannheim     

降钙素在甲状腺髓样癌诊治中的意义及甲状腺髓样癌临床特点分析

探讨降钙素 (CT)在甲状腺髓样癌 (MCT)诊断和治疗中的意义 ,并回顾分析MCT的临床特点。以手术和病理证实的 31例MTC为对象 ,起病年龄 (4 2 8± 6 7) (2 1～ 6 7)岁 ,以年龄和性别相匹配的骨质疏松症患者为对照。血清CT和甲状旁腺素采用放射免疫法检测。血钙、磷、碱性磷酸酶采用自动生化分析仪测定。 31例患者中男性 19例 ,女性 12例 ;散发型 2 2例 (71% ) ,合并多发性内分泌腺瘤病 (MEN) 9例 (2 9% ) ;多于中青年起病。首发症状主要是逐渐长大的颈前肿物 ,临床症状为不同程度的消耗症状、腹泻、腹痛、多汗、声音改变等。合并MEN的尚有高儿茶酚胺的表现。甲状腺均触及肿大 ,质硬、活动度差 ,7例有颈淋巴结肿大。患者人均手术 (1 4± 0 7) (1～ 4 )次 ,病理以甲状腺滤泡旁细胞增生为特点 ,降钙素免疫组织化学染色均阳性 (6例 ,10 0 % )。肿瘤易于复发 (4 1 9% )和转移(5 4 8% )。术前和复发时CT水平为 (14 6 5 2 3± 1314 0 1)ng/L ,明显高于正常和骨质疏松对照组 (P <0 0 0 1) ,术后为(388 99± 374 95 )ng/L ,明显低于术前水平 (P <0 0 1) ,CT与血钙、磷无明显相关性。对于逐渐增大、质硬、伴颈淋巴结肿大的甲状腺肿物 ,应谨惕MCT的可能。血清CT是敏感而特异的MCT标志物 ,对于MCT的早期诊断、     

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.     

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 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.     

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     

Secretion of calcitonin and carcinoembryonic antigen in long-term organ culture of human medullary thyroid carcinoma: Biochemical and immunocytochemical studies

Summary Tissue cultures of four C-cell carcinomas (medullary thyroid carcinoma, MTC) were prepared to study the basal and stimulated calcitonin (CT) and carcinoembryonic antigen (CEA) release. Immunohistological staining of the explants for CT and CEA have been performed after various periods of culture. These MTC explants were able continuously to release CT and CEA for periods up to 157 days. The spontaneous CT and CEA release decreased sharply during the 1st week of culture, then remained nearly constant over the observation period. The CEA/CT secretion ratio slightly declined during long-term culture; CEA release seems to drop earlier than CT production. CT and CEA could be detected in the same cells by immunocytochemical technique. The septal tissue consisting of dense connective tissue and amyloid produced by tumor cells seemed to increase during long-term culture. CT, but not CEA, was stimulated by pentagastrin (10^–5 M), glucagon (6×10^–6 M), and dose related by calcium (2.5–20 mM) in vitro. The MTC explant organ long-term culture proved to be a useful model for studies of human CT and CEA secretion.Abbreviations MTC medullary thyroid carcinoma - CT calcitonin - CEA carcinoembryonic antigen - MEN multiple endocrine neoplasia - PAP peroxidase anti-peroxidase     

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.     

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.     

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