Ultrastructural features of "solid cell nest" of the human thyroid gland: a study of 8 cases

The ultrastructural features of solid cell nests (SCN), made of squamous cells, and associated calcitonin cells (C cells), of the thyroid gland were studied in only a few cases in humans. A study was performed on 8 paraffin-embedded SCN, postembedded in Epon, to look for their ultastructural features. Immunohistochemical analysis using calcitonin antibody was performed on semithin sections of SCN to explore the presence of C cells. Three cases (37.5%) of SCN were positive for calcitonin, and electron-dense secretory granules were observed in the cytoplasm. In two of these cases, an increased number of C cells in the adjacent thyroid parenchyma was observed. The presence of ciliated and lymphoid cells, in addition to intracytoplasmic microvacuolar and microfollicular (microglandular) structures, was noticed. Ciliated cells have already been reported in embryonic rests of human and animals, but ultrastructurally for the first time in human SCN. The presence of microfollicular structures, intracytoplasmic microvacuolar, secretory granules features, and ciliated cells, in addition to lymphoid cell, suggests the existence of a common ultimobranchial stem cell for C cells or for one or more cell types of the thyroid gland.     

C cell carcinoma of the thyroid. Follicular variant

A case of C cell carcinoma of the thyroid with an unusual follicular growth pattern of the cancerous C cells is described. The primary tumor consisted of a mixture of medullary and follicular features while the metastatic foci in the lymph nodes and liver displayed only a medullary arrangement. Histochemical study disclosed numerous argyrophilic cells in both the follicular and medullary parts. These cells were immunohistochemically positive for calcitonin, calcitonin gene-related peptide (CGRP) and other peptides as well as carcinoembryonic antigen (CEA), but negative for thyroglobulin. Radioimmunoassay done on the tissue extract revealed a high content of calcitonin. Electron microscopy showed small intracytoplasmic secretory granules and, in the follicular lining cells, formation of microvilli. A minor component consisting of glandular structures has been reported in medullary carcinoma of the thyroid, suggesting a potentiality for glandular differentiation of the C cells. In equivocal cases, immunohistochemical examination for calcitonin and thyroglobulin is essential for accurate diagnosis of thyroid carcinoma.     

C Cell Carcinoma of the Thyroid Follicular variant

A case of C cell carcinoma of the thyroid with an unusual follicular growth pattern of the cancerous C cells is described. The primary tumor consisted of a mixture of medullary and follicular features while the metastatic foci in the lymph nodes and liver displayed only a medullary arrangement. Histochemical study disclosed numerous argyrophilic cells in both the follicular and medullary parts. These cells were immunohistochemically positive for calcitonin, calcitonin gene-related peptide (CGRP) and other peptides as well as carcinoembryonic antigen (CEA), but negative for thyroglobulin. Radioimmunoassay done on the tissue extract revealed a high content of calcitonin. Electron microscopy showed small intracytoplasmic secretory granules and, in the follicular lining cells, formation of microvilli. A minor component consisting of glandular structures has been reported in medullary carcinoma of the thyroid, suggesting a potentiality for glandular differentiation of the C cells. In equivocal cases, immuno-histochemical examination for calcitonin and thyroglobulin is essential for accurate diagnosis of thyroid carcinoma. Acta Pathol Jpn 39: 393-399, 1989.     

The ultimobranchial gland and congenital thyroid abnormalities in man

This study was carried out to investigate the fate of the ultimobranchial contribution to the thyroid in man when the thyroid lobe is not fully descended. Thyroid abnormalities were recorded in 41 of 29,000 autopsies at the London Hospital--a prevalence of 1.41/1000. The 18 major abnormalities included four cases of lingual thyroid, in two of which cystic structures were noted in the neck in the region of the upper parathyroid. Three further cases of lingual thyroid with upper parathyroid cysts were collected from other sources. The multilobulated cystic structures were up to 1.5 cm in diameter and showed a variety of histologic features. In four cases there were glandular nodules of up to 1 mm across lying in the intercystic connective tissue. These nodules showed solid areas of irregularly distributed cells that stained positively for calcitonin and calcitonin gene-related peptide, intermingled with, and sometimes apposed to, follicular structures that showed follicular cells and colloid that stained for thyroglobulin. This study has provided conclusive evidence that the ultimobranchial body contributes both C cells and follicular cells to the thyroid in man, has documented the prevalence of congenital defects of thyroid development, and has described the human ultimobranchial gland as showing a wide developmental potential which may have implications in the histogenesis of thyroid neoplasia.     

Secretory activity in medullary thyroid carcinoma: a cytomorphological and immunocytochemical study

Medullary thyroid carcinoma (MTC) is a relatively rare thyroid malignancy of C-cell origin that secretes calcitonin. Although its varied cytomorphologic features are well described in literature, very little is mentioned about the morphologic manifestation of its secretory activity. This study, based on nine fine needle aspiration (FNA) samples from eight MTC patients, is an attempt to present the varied cytomorphologic features suggesting secretory activity in MTC as observed in Papanicolaou and MGG stained FNA smears and correlate them with the immunocytochemical (ICC) staining for calcitonin performed on FNA smears and the serum calcitonin values. The average number of cells in these nine samples was as follows: oval/triangular/plasmacytoid (56.7%), small round (23.6%), spindle-shaped (12.7%), and miscellaneous (7.1%). The cytomorphological features suggesting secretory activity, viz., fine cytoplasmic vacuoles, azurophillic granules, marginal vacuoles, and intracytoplasmic lumina (ICL) with secretions were present in eight, eight, five, and six samples, respectively. Material likely to be amyloid, based on morphological features, was present extracellularly in three samples and both intracellularly and extracellularly in six samples. Immunocytochemically, all the nine samples stained for calcitonin and all the three stained for chromogranin showed positive cytoplasmic reaction in the neoplstic cells. The background amyloid (in six samples), the coarse cytoplasmic granules (in two samples), and the contents of ICL (in one sample) were found to be positively stained for calcitonin. The intracytoplasmic secretory material appeared to be diffusing out of some cells both in the routine MGG stained smears and in the smears stained for calcitonin. Histopathology reports of seven samples in six patients confirmed the cytodiagnosis of MTC in all. Baseline serum calcitonin values in three cases and postoperative serum calcitonin levels during follow-up in three others were high. Thus, our study highlighted the morphological manifestations of secretory activity in MTC and the nature of secretory material as calcitonin, supported by immunocytochemical staining and serum calcitonin level.     

Branchial-like cysts of the thyroid associated with solid cell nests

Presented herein is the case of a 65-year-old man with a 20 year history of thyroid hypofunction. On sonography a cystic lesion 4 x 4 x 5 cm in largest diameter was found, replacing most of the right lobe of the thyroid gland. Microscopically, the lesion was composed of labyrinth-like cystic structures (LCS) lined by a few layers of benign-appearing squamous cells and filled by mucinous material. Adjacent to the cyst walls were discontinuous patches of a lymphoid tissue, composed of haloed centrocyte-like cells or germinal centers mostly depleted of germinal cells. Additionally, there were numerous squamous cell nests equivalent to solid cell nests (SCN), all of which were surrounded by a similar-looking lymphoid tissue. Rare SCN were thus cystically changed and contained a small amount of mucus. The SCN communicated with the LCS: the former represented the most distal outpouchings of the latter. The epithelial structures were surrounded by a loose collagenous adipocytic stroma with plump fibroblasts, which resembled the stroma often seen in lateral neck cysts associated with structures such as cartilage, accessory salivary gland tissues, cysts and accessory thyroid and thymus. Immunohistochemically, all lesional elements were negative for calcitonin and thyroglobulin. The results of the paper suggest that branchial cleft-like cyst have an origin in the ultimobranchial body.     

A study on the relationship between solid cell nests and mucoepidermoid carcinoma of the thyroid

Mucoepidermoid carcinoma of the thyroid (MECT) has been recently recognized as a pathological entity. The origin of MECT is unknown but the morphology of this tumour closely resembles features seen in the ultimobranchial body (UB) vestiges. Recent studies in man have shown strong evidence that the so-called solid cell nests (SCN) of the thyroid may correspond to the human UB vestiges. To investigate whether these vestiges are the site of origin of this tumour a comparative study on SCN and MECT was undertaken. One hundred autopsied thyroids cut at 2-3 mm intervals were studied for the presence of SCN. Histochemical (H & E, Alcian blue-PAS, Mayer mucicarmine) and immunohistochemical studies (calcitonin, epidermal keratin) were performed in SCN and four cases of MECT. Sixty percent of thyroids were found to have SCN. They were mainly composed of epidermoid-like cells arranged in solid structures or lining cystic cavities, tubular and follicular structures. Solid clusters usually showed lumina containing PAS-positive and mucin-positive cell debris. Mucin stains also revealed mucinous cells placed around lumina filled by mucosubstances. Characteristic PAS-positive rounded bodies were found filling lumina as well as within some apical epidermoid-like cells, mucinous cells and cell debris. An obvious transition between these cells, cell debris and mucosubstances filling the lumina was noticed; suggesting degenerative changes undergone by the epidermoid-like cell. MECT basically presented all histological and histochemical features shown by SCN, furthermore, calcitonin containing cells were observed in 54% of SCN, while a metastatic MECT also showed scattered C cells within solid islands. The presence of epidermal keratin in all SCN and MECT, together with the previous findings, are strong evidence that MECT could originate in the SCN or human UB vestiges.     

Solid cell nests and thyroid pathologies. Retrospective study of 1,390 thyroids

Solid Cell Nests (SCN) of the thyroid gland were considered as embryonic remnants or as squamous metaplasia of follicular epithelium. In a retrospective study of 1 390 thyroids, SCN were found in 9.7 % of thyroids (16 % men and 8 % women, chi(2) : p <0, 01). The number of SCN rises with increasing number of sections examined. No statistical differences were found with age or thyroid disorders and presence of SCN, excluding the metaplastic theory. SCN contained in 38 % of cases, neuroendocrine cells (calcitonin and/or calcitonin gene related peptide, chromogranin A) and thyroglobulin cells was observed in 78.3 % of SCN. The different cell types of SCN fitted with the ultimobranchial remnant theory. Thus, some rare carcinomas (like mixed medullary and vesicular carcinoma or mucoepidermoid carcinoma) might originate from SCN.     

C cell hyperplasia and carcinoma developing in sheep with experimentally-induced lymphosarcoma.

Two cases of C cell hyperplasia and one case of C cell carcinoma of the thyroid glands were bilaterally recognized in 11 sheep with experimentally-induced lymphosarcoma. The serum calcium concentration in the C cell carcinoma case was slightly increased above the normal concentration of around 9 mg per dl. Bilateral C cell hyperplasia also developed in the thyroid lobes of the C cell carcinoma case. Immunohistochemically, hyperplastic C cells and tumour cells were positive for calcitonin, calcitonin gene-related peptide, chromogranin A and neurone-specific enolase. No amyloid deposition nor multiple endocrine neoplasia was demonstrated in any of the cases. Ultrastructurally, many secretory granules were observed in the cytoplasm of neoplastic cells constituting the C cell carcinoma and in the hyperplastic C cells.     

Immunoreactive calcitonin in amyloid fibrils of medullary carcinoma of the thyroid gland. An immunogold staining technique

A lymph node containing metastatic medullary carcinoma of the thyroid gland was examined immunohistochemically for the presence of calcitonin by light and electron microscopy. Electron microscopy showed dense, selective labeling of the tumor-associated amyloid fibrils and labeling of the scanty intracytoplasmic neurosecretory granules. By light microscopy, a few tumor cells showed strong staining, whereas the amyloid fibrils showed equivocal staining.     

Medullary (C cell) carcinoma of the thyroid with features of follicular oxyphilic cell tumours

During the last few years the spectrum of histological features seen in tumours of C cell origin has broadened and, among other variants, papillary and glandular forms have been recognized. Seven cases are now reported of medullary carcinoma with features of oxyphilic follicular cell tumours. These cases were studied with routine techniques and an immunolocalization method using antibodies to calcitonin and thyroglobulin. The tumours were mainly composed of well-demarcated eosinophilic cells of variable size arranged in trabecular, solid and follicular structures. One of the cases was negative for calcitonin but displayed strong diffuse argyrophilia and amyloid deposits; two amyloid-free tumours revealed argyrophil granules and were positive for calcitonin, the immunoreaction being inconspicuous in one however. Apart from trapped normal thyroid follicles, thyroglobulin was absent in the tumours. It is concluded that medullary carcinoma should be considered in the differential diagnosis of thyroid oxyphilic cell tumours, even when showing glandular differentiation, and that immunolocalization techniques using calcitonin and thyroglobulin in combination with methods for demonstration of argyrophil granules and amyloid are essential for accurate diagnosis of this type of medullary carcinoma of the thyroid.     

Electron microscopic study on the development of the chicken ultimobranchial glands, with special reference to innervation of C cells

The development of chicken ultimobranchial glands was studied by electron microscopy. As early as at 8 days of incubation, some cells contained a few secretory granules, although most of the ultimobranchial cells were undifferentiated. Single axons or small bundles of axons were occasionally detected in close contact with the ultimobranchial cells. Subsequently, immature C cells gradually increased in number with age. At 12 days of incubation, the developing C cells, which contained some secretory granules from 60 to 200 nm in diameter, occupied the greater part of the gland. The cells were oval, elongated or irregular in shape and frequently gave rise to long cytoplasmic processes that touched other C cells. Numerous axons enveloped with Schwann cell processes occurred in close vicinity to C cells. At 14 days of incubation, the cytoplasmic processes of C cells reached their maximum number and size. Desmosome-like membrane specialization was observed at the contact between the processes and cell bodies of other C cells, while numerous microtubules were arranged in parallel to the long axes of the processes, and secretory granules were distributed along them. Thus, the C cells at these stages seem to regulate other homologous cells by direct contact. Axon terminals, which contained small, clear and large, densecored vesicles, were first found in direct contact with the surface of C cells in 14-day-old embryos. Subsequently, the cytoplasmic processes of C cells progressively decreased, while nerve fibers continued to increase in the ultimobranchial glands. At the late stages of embryonic development, many C cells displayed an oval outline and increased number and size of secretory granules. At hatching, many C cells were filled with large secretory granules ranging from 200 to 700 nm in diameter (average 300 nm). Some cells were still elongated or irregular in shape and contained small secretory granules, 60–200 nm in diameter.     

Ultrastructure of primary squamous cell carcinoma of the submandibular gland

Primary squamous cell carcinoma of the submandibular gland is a rare tumor. In this report, the histological and ultrastructural features of a case of primary squamous cell carcinoma arising in the left submandibular gland is presented. Light microscopically, the tumor consisted of well differentiated keratinizing squamous cell nests. Ultrastructurally, the tumor cells were oval or spindle-shaped, and several tumor cells had intracytoplasmic desmosome-like structures, resembling intercellular desmosomes. The majority of the tumor cells contained a large number of intermediate filaments (tonofilaments). Intercellular desmosomes were well developed. No secretory granules were found. These ultrastructural features may enable us to distinguish primary squamous cell carcinoma from mucoepidermoid carcinoma which is often misdiagnosed as squamous cell carcinoma.     

Ultrastructure in C cell hyperplasia in asymptomatic patients with hypercalcitoninemia and a family history of medullary thyroid carcinoma

C cell hyperplasia and occult medullary carcinoma of the thyroid in asymptomatic individuals at genetic risk can be detected by measurement of serum calcitonin concentrations before and after stimulation with a secretagogue. Electron microscopy was used to confirm the presence of C cell hyperplasia after demonstration of elevated serum calcitonin values in three asymptomatic young women from two affected kindreds. Nodules of hyperplastic cells were observed in each of the three thyroids and were composed of two types of cells, one rich in secretory granules and the other in mitochondria. In one thyroid relatively large nodules also contained extracellular deposits of amyloid. Although the presence of the two types of cells and amyloid deposits is characteristic of medullary carcinoma, there was no evidence that the C cell nodules were malignant. However, such nodules may represent a certain stage in the development of medullary carcinoma of the thyroid. We believe, therefore, that electron microscopy can demonstrate incipient C cell neoplasia in needle biopsy specimens. Confirmation of C cell neoplasia is desirable for positive diagnosis and hence for genetic counseling in patiens with a family history of the disease.     

Medullary cancer of the thyroid gland and its possible relations to carcinoids

Summary The ultrastructural study of a medullary cancer of the thyroid gland revealed some unusual features. The stroma of the tumor did not contain amyloid. An abundant amount of intracytoplasmic microfilaments was observed in the tumor cells, sometimes displacing the various organelles. The most prominent feature was the presence of very dense, pleomorphic (biconcave) secretory granules, measuring an average of 250 mµ in their longest diameter. Mainly because of the type of secretory granules, this tumor showed a peculiar resemblance to ileal carcinoids. The possible significance of this finding is discussed.     

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.     

Medullary carcinoma of the thyroid with carcinoid-like features.

AIMS: To show that medullary carcinomas of the thyroid are morphologically indistinguishable from gut carcinoids: the value of histochemistry in their identification and differential diagnosis from metastatic carcinoid tumours to the thyroid and some follicular cell neoplasms. METHODS: 15 thyroid medullary carcinomas with features of gut carcinoids were histochemically studied for the presence of argyrophil and argentaffin granules, and calcitonin, thyroglobulin, and serotonin immunoreaction. RESULTS: Histological features of midgut (classic) carcinoids were observed in two tumours, foregut carcinoids in 12, and hindgut carcinoids in one. All tumours showed, to a greater or lesser extent, a calcitonin immunoreaction and argyrophilia. These markers were present only in a small area showing a classic pattern of thyroid medullary carcinoma in the hindgut carcinoid-like neoplasm. Argentaffin granules and serotonin immunostaining occurred in occasional cells from four foregut carcinoid-like tumours. Thyroglobulin was not expressed in all cases and amyloid stroma was expressed in three. CONCLUSIONS: In some cases a diagnosis of metastatic carcinoid tumour to the thyroid can be considered only after ruling out clinically and histochemically medullary carcinoma of the thyroid. Immunolocalisation techniques are also essential for the differentiation between medullary carcinoma and thyroid follicular cell neoplasms that resemble carcinoid tumours. It is proposed that this tumour variant to be incorporated into current classifications as another histological subtype of C cell carcinoma.     

Piriform sinus fistula and the ultimobranchial body

Piriform sinus fistulae are an underlying abnormality common in patients with acute suppurative thyroiditis. The fistulae arise from the hypopharynx, and end in or adjacent to the thyroid lobe. These congenital fistulae seem to be remnants of one of the pharyngeal pouches in embryonic development, but their exact origin is still controversial. Resected specimens of the thyroid glands and fistulae from 15 patients were examined immunohistochemically with rabbit antisera to human calcitonin and thyroglobulin. The fistulae were lined by squamous, columnar or ciliated epithelium, and sometimes formed branches in the thyroid lobe. Near the branches solid cell nests existed. Mucous glands, follicular structures and thymic tissue were found in the fistula. The follicular structures stained for thyroglobulin. Immunostaining for calcitonin revealed aggregates of many C cells in the thyroid near the fistula. A few calcitonin-positive cells were also found in the fistula. These findings, along with the anatomical relation of the fistulae to major structures of the neck, strongly suggest that the fistulae are remnants related to the ultimobranchial body, and that the fistulae trace the migration route of the ultimobranchial body to the thyroid gland.