Ultimobranchial body cyst in an adult horse: clinical, histopathologic, and immunohistochemical features.

A 9-y-old Mangalarga Marchador gelding was referred to a veterinary hospital because of a swelling on the upper right side of the neck. Ultrasound examination revealed a multilocular structure adjacent to the thyroid gland with low echogenic content suggestive of fluid. The mass was removed surgically. Histologically, the cystic cavities in the surgical sample were filled with abundant eosinophilic secreta and lined by cuboidal, segmentally ciliated, columnar epithelium with interspersed goblet cells. Segmental crowding of the multilayered lining of the cyst was noted. Immunohistochemistry suggested the presence of both C cells and follicular cells, given the positivity of the immunomarkers calcitonin and TTF-1, respectively. The histogenesis of ultimobranchial cysts is uncertain. Based on clinical, histopathologic, and immunohistochemical identification, the cystic structure in this case is compatible with an ultimobranchial body cyst.

C-cell differentiation in the wall of an aberrant ultimobranchial sinus in the thyroid gland of an old rat.

BACKGROUND: In mammals, the thyroid gland possesses two types of endocrine cells, follicular cells and C cells, which have different functions but share a similar endodermal origin (although from different regions of the primitive pharynx). Specifically, follicular cells derive from the ventral pharyngeal floor, while C cells derive from the fourth pair of pharyngeal pouches through the ultimobranchial bodies (UBBs). Disruptions to human midline thyroid morphogenesis are relatively frequent and known as thyroid dysgenesis, which is the leading cause of congenital hypothyroidism. In contrast, fourth branchial apparatus anomalies are very rare clinical entities. OBJECTIVES: The aim of this study was to analyze the morphological features and the immunohistochemical pattern of an aberrant ultimobranchial remnant, align with its persistent contribution to the formation of new C cells. METHODS: The thyroid gland of an old rat was serially sectioned and immunostained for the following markers: calcitonin, thyroglobulin, cytokeratins, PCNA, P63, E-cadherin, beta-tubulin and CD3. RESULTS: We detected a spontaneous congenital defect in the organogenesis of the UBB in an old rat, giving rise to an 'ultimobranchial sinus', which was accompanied by thymic tissue and an abscess. The epithelium contained basal/stem cells and contributed to the formation of abundant C cells and scarce follicular cells. CONCLUSIONS: The ultimobranchial sinus is an exceptional finding for representing the first spontaneous abnormality in the development of UBB reported in rats, and the opportunity to observe sustained C-cell differentiation from stem cells in an old rat. These findings are consistent with a common origin of both C cells and follicular cells from UBB.

Morphological, histological and ultra-structural studies on the ultimobranchial body of goat (Capra hircus).

Ultimobranchial body (UBB) remnant was considered as an enigma till the last few years, then it was recognized as a necessary organ where it is the origin of the parafollicular cells. The samples were fixed and processed for the histological and electron microscopic examination. Macroscopically, the UBB remnant appeared as a white mass at the end of the cranial one-third of the thyroid lobe. It was composed of solid cell nest, cluster of cells and small thyroid follicles. Transmission electron microscope showed some round cells containing euchromatic nuclei, numerous parafollicular cells with darkly stained granules and paler ones. It also showed some mast cells with heterochromatic nuclei and large darkly stained granules. The parafollicular cells were distributed throughout the thyroid gland but concentrated within the UBB remnant. To our knowledge, our findings represent very unique histological manifestations specially the ultra-structural ones which revealed an original finding about the new clear type of cells suggested to be a UBB remnant and ensure those of the light microscope.

Thyroid Adenoma of Probable Ultimobranchial Body Origin: A Case Report.

Solid cell nests are generally believed to represent remnants of the ultimobranchial body, which can be found in the normal thyroid gland, occasionally associated with other branchial pouch remnants such as salivary gland, cartilage, and adipose tissue. We describe the case of a 44-year-old man incidentally found to have a large tumor in the left lobe of the thyroid. The tumor was a circumscribed growth consisting of distinctly lobulated proliferation of solid to cystic epidermoid cell nests and thyroid follicles in a fibromatous stroma, which merged into abundant adipose tissue and focally myxoid matrix. The solid epidermoid cell nests resembled solid cell nests and exhibited a p63+, GATA3+, galectin-3+, TTF1-, PAX8-, thyroglobulin- phenotypes, while the follicles were p63-, GATA3-, galectin-3-, TTF1+, PAX8+, and thyroglobulin+. RAS mutations were not found. This thyroid tumor may represent a hitherto undescribed "ultimobranchial body adenoma" in human.

Thyroid Tubercle of Zuckerkandl May Not Arise from the Ultimobranchial Body: Results from Histological Analysis.

Thyroid tubercle of Zuckerkandl (TZ) is a nodule arising from the posterolateral thyroid, considered to be a remnant of the ultimobranchial body (UB). Considering that C cells and solid cell nests also arise from the UB, we hypothesized that these would be present in the TZ. We examined the presence of C cells and solid cell nests in the TZ using the histological analyses of 21 patients with grade 2 or 3 TZs following Pelizzo's grading system. Out of 21 TZs, 19 (90.5%) were located in the right lobe of the thyroid. Microscopically, solid cell nests were found within the TZ in 1 case (4.8%), and within the main thyroid tissues in 3 cases (14.3%). Calcitonin-positive C cells were scattered within the TZ in 1 case (4.8%), and within the main thyroid tissue in 15 cases (71.4%). The distribution of C cells within the main thyroid tissue was denser than that within the TZ. The above-mentioned results indicated the lack of C cells and solid cell nests in the TZ. Although the TZ may have an embryological origin different from that of ordinary thyroid tissue, it is unlikely that the remnants of the UB are involved in the formation of the TZ.

Follicular cell lineage in persistent ultimobranchial remnants of mammals.

It has been a subject of much debate whether thyroid follicular cells originate from the ultimobranchial body, in addition to median thyroid primordium. Ultimobranchial remnants are detected in normal dogs, rats, mice, cattle, bison and humans and also in mutant mice such as Eya1 homozygotes, Hox3 paralogs homozygotes, Nkx2.1 heterozygotes and FRS2α2F/2F. Besides C cells, follicular cell lineages immunoreactive for thyroglobulin are located within these ultimobranchial remnants. In dogs, the C cell complexes, i.e., large cell clusters consisting of C cells and undifferentiated cells, are present together with parathyroid IV and thymus IV in or close to the thyroid lobe. In addition, follicular cells in various stages of differentiation, including follicular cell groups and primitive and minute follicles storing colloid, are intermingled with C cells in some complexes. This review elaborates the transcription factors and signaling molecules involved in folliculogenesis and it is supposed why the follicular cells in the ultimobranchial remnants are sustained in immature stages. Pax8, a transcription factor crucial for the development of follicular cells, is expressed in the fourth pharyngeal pouch and the ultimobranchial body in human embryos. Pax8 expression is also detected in the ultimobranchial remnants of Eya1 and Hes1 null mutant mice. To determine whether the C cells and follicular cells in the ultimobranchial remnants consist of dual lineage cells or are derived from the common precursor, the changes of undifferentiated cells in dog C cell complexes are examined after chronically induced hypercalcemia or antithyroid drug treatment.

Restricted localization of ultimobranchial body remnants and parafollicular cells in the one-humped camel (Camelus dromedarius).

Parafollicular cells (C-cells) exist within the thyroid glands and display different distributions within the glands among mammalian species. In the one-humped camel (Camelus dromedarius), localization of the C-cells remains under debate. We herein investigated appearance of C-cells and the remnants of the ultimobranchial body, origin of C-cells, in the thyroid glands of one-humped camels. Macroscopically, a white mass was present at one-third the length from the cranial end of the thyroid glands where the cranial thyroid artery entered. In addition, large fossae were frequently found adjacent to the white mass. Histologically, the mass was mainly composed of connective tissues, thyroid follicles, and two types of cell clusters: one was composed of cells with clear cytoplasm and the other was composed of non-keratinized epidermoid cells. The mass and the fossae contained p63-positive cells, indicating that they consisted of ultimobranchial body remnants. Calcitonin was expressed in cells with clear cytoplasm, which were localized just beneath the fossae and in the cell clusters of the white mass. C-cells also resided in both subfollicular and interfollicular spaces adjacent to the white mass, but gradually decreased toward the periphery. C-cells tended to display round shapes in the ultimobranchial body remnants and subfollicular spaces, and spindle shapes in interfollicular spaces. In conclusion, we demonstrated that the ultimobranchial body remnants were limited to the region around the entrance of cranial thyroid artery and vein, and C-cells were mainly concentrated within and around the ultimobranchial body remnants.

Solid Cell Nests Within a Parathyroid Gland-Report of an Exceptional Case.

The ultimobranchial body (UBB) denotes the cellular mass originating from the fourth branchial pouch, which migrates from the neural crest and infolds within the middle and upper poles of the thyroid lobes, thereby establishing the presence of calcitonin-secreting parafollicular C cells. In various numbers, UBB remnants (entitled "solid cell nests", or SCNs) are found in thyroid glands examined histologically. However, despite the close embryological relation between the UBB and the superior parathyroid glands, intraparathyroidal SCNs have to our knowledge not been previously reported. Here, we describe a patient presenting with a papillary thyroid carcinoma with central and lateral lymph node metastases. Upon postoperative analysis, an unintentionally removed parathyroid gland was observed adjacent to the superior aspect of the right thyroid lobe. Within a 0.6 × 0.5-mm area of the parathyroid gland, solid nests composed of epithelial cells with oval and slightly elongated nuclei were seen. The cells were positive for p40, p63, and GATA3, but negative for PTH. The final diagnosis was a SCN entrapped within the parathyroid gland. Empirically, we have not previously observed SCNs within the parathyroid glands. To our knowledge, our finding thus constitutes a very unusual histological manifestation, and could indicate an underlying aberrancy during embryogenesis given the close anatomical relationship between the UBB and the superior parathyroid glands.

Positivity for GATA3 and TTF-1 (SPT24), and Negativity for Monoclonal PAX8 Expand the Biomarker Profile of the Solid Cell Nests of the Thyroid Gland.

Solid cell nests (SCNs) are usually distinguished on conventional H&E-stained sections; however, the morphological heterogeneity in SCNs and hyperplasia of these ultimobranchial body remnants can mimic other diagnostic entities including but not limited to papillary microcarcinoma. In order to confirm the thyroid follicular epithelial origin and exclude the possibility of SCNs, most diagnosticians use immunohistochemical biomarkers of thyroid follicular epithelial cells and/or those of SCNs. While the expression profile of monoclonal PAX8 has not been reported previously in SCNs, the status of TTF-1 expression using the 8G7G3/1 clone has been inconsistent among several studies. Given the potential diagnostic pitfalls, this series investigated the expression profile of GATA3, monoclonal PAX8, and TTF-1 (SPT24), along with p63, p40, monoclonal calcitonin, monoclonal CEA, and HBME-1 in a tissue microarray (TMA) of 56 SCNs. SCNs were all diffusely and strongly positive for TTF-1 (SPT24), p63, and p40, and were negative for monoclonal PAX8 and calcitonin. Positivity for GATA3 and monoclonal CEA was identified in 41 (73.2%) and 36 (64.3%) of SCNs. In addition, 18 (32.1%) SCNs displayed HBME-1 reactivity. These findings expand the immunohistochemical correlates of SCNs by demonstrating positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal PAX8. The identification of monoclonal CEA expression and HBME-1 in SCNs also underscores the limitations of these select biomarkers in the distinction of C cell proliferations and papillary microcarcinoma, respectively. The findings of this series also suggest that positivity for TTF-1 (SPT24) alone should not be used to confirm the thyroid follicular epithelial origin. Therefore, the combined use of TTF-1 (SPT24) and monoclonal PAX8 in association with p63 or p40 provides an accurate distinction of SCNs.

Morphological and molecular evolution of the ultimobranchial gland of nonmammalian vertebrates, with special reference to the chicken C cells.

This review summarizes the current understanding of the nonmammalian ultimobranchial gland from morphological and molecular perspectives. Ultimobranchial anlage of all animal species develops from the last pharyngeal pouch. The genes involved in the development of pharyngeal pouches are well conserved across vertebrates. The ultimobranchial anlage of nonmammalian vertebrates and monotremes does not merge with the thyroid, remaining as an independent organ throughout adulthood. Although C cells of all animal species secrete calcitonin, the shape, cellular components and location of the ultimobranchial gland vary from species to species. Avian ultimobranchial gland is unique in several phylogenic aspects; the organ is located between the vagus and recurrent laryngeal nerves at the upper thorax and is densely innervated by branches emanating from them. In chick embryos, TuJ1-, HNK-1-, and PGP 9.5-immunoreactive cells that originate from the distal vagal (nodose) ganglion, colonize the ultimobranchial anlage and differentiate into C cells; neuronal cells give rise to C cells. Like C cells of mammals, the cells of fishes, amphibians, reptiles, and also a subset of C cells of birds, appear to be derived from the endodermal epithelium forming ultimobranchial anlage. Thus, the avian ultimobranchial C cells may have dual origins, neural progenitors and endodermal epithelium. Developmental Dynamics 246:719-739, 2017. © 2017 Wiley Periodicals, Inc.

Immunohistochemical profiling of the ultimobranchial remnants in the rat postnatal thyroid gland.

Ultimobranchial (UB) remnants are a constant presence in the thyroid throughout rat postnatal life; however, the difficulty in identifying the most immature forms from the surrounding thyroid tissue prompted us to search for a specific marker. With that objective, we applied a panel of antibodies reported to be specific for their human counterpart, solid cell nests (SCNs), using double immunohistochemistry and immunofluorescence. Our results demonstrated that cytokeratin 34ßE12 and p63 are highly sensitive markers for the immunohistologic screening of UB-remnants, independently of their maturity or size. Furthermore, rat UB-follicles (UBFs) coincided with human SCNs in the immunohistochemical pattern exhibited by both antigens. In contrast, the pattern displayed for calcitonin and thyroglobulin differs considerably but confirm the hypothesis that rat UB-cells can differentiate into both types of thyroid endocrine cells. This hypothesis agrees with recent findings that thyroid C-cells share an endodermic origin with follicular cells in rodents. We suggest that the persistence of p63-positive undifferentiated cells in UB-remnants may constitute a reservoir of basal/stem cells that persist beyond embryogenesis from which, in certain unknown conditions, differentiated thyroid cells or even unusual tumors may arise.

Morphology and relationships of ultimobranchial body with pharyngeal pouches

The ultimobranchial body in humans is still controversial and different theories have been put forward. The aim of this study was to clarify the topographical anatomy of the ultimobranchial body and surrounding tissue during early development. Human embryos at 5-7 weeks of development were used for morphological observation. During the early stages, the sections displayed a ladder-like arrangement of the second to fourth endodermal pouches. The fourth pouch was located in front of the nodosa ganglion. The bilateral fifth pharyngeal pouches protruded anterolaterally to form a Ushaped lumen surrounding the arytenoid swelling. During the middle stages, the third pharyngeal pouch was identified near the fourth pharyngeal artery and the fourth pharyngeal pouch was located anterior to the parathyroid gland IV. We identified a cyst-like structure that is composed of a cell cluster facing to a small lumen as the ultimobranchial body. During the late stages, the lateral thyroid arising from the fourth pharyngeal pouch was located medial to the common carotid artery and joined to dorsal surface of the thyroid gland anlage. The thymus anlage arising from the third pharyngeal pouch was an independent structure that was located lateral to the common carotid artery. However, the ultimobranchial body had disappeared and did not integrate in the thyroid gland. We concluded that (1) the thymus originates from the third pharyngeal pouch; (2) the lateral thyroid originates from the fourth pharyngeal pouch; (3) the ultimobranchial body originates from the fifth pharyngeal pouch

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Temporal and spatial requirements for Hoxa3 in mouse embryonic development.

Hoxa3(null) mice have severe defects in the development of pharyngeal organs including athymia, aparathyroidism, thyroid hypoplasia, and ultimobranchial body persistence, in addition to defects of the throat cartilages and cranial nerves. Some of the structures altered in the Hoxa3(null) mutant embryos are anterior to the described Hoxa3 gene expression boundary: the thyroid, soft palate, and lesser hyoid horn. All of these structures develop over time and through the interactions of multiple cell types. To investigate the specific cellular targets for HOXA3 function in these structures across developmental time, we performed a comprehensive analysis of the temporal and tissue-specific requirements for Hoxa3, including a lineage analysis using Hoxa3(Cre). The combination of these approaches showed that HOXA3 functions in both a cell autonomous and non-cell autonomous manner during development of the 3rd and 4th arch derivatives, and functions in a neural crest cell (NCC)-specific, non-cell autonomous manner for structures that were Hoxa3-negative by lineage tracing. Our data indicate that HOXA3 is required for tissue organization and organ differentiation in endodermal cells (in the tracheal epithelium, thymus, and parathyroid), and contributes to organ migration and morphogenesis in NCCs. These data provide a detailed picture of where and when HOXA3 acts to promote the development of the diverse structures that are altered in the Hoxa3(null) mutant. Data presented here, combined with our previous studies, indicate that the regionally restricted defects in Hoxa3 mutants do not reflect a role in positional identity (establishment of cell or tissue fate), but instead indicate a wider variety of functions including controlling distinct genetic programs for differentiation and morphogenesis in different cell types during development.

Ultimobranchial gland respond in a different way in male and female fresh water teleost Mastacembelus armatus (Lacepede) during reproductive cycle.

The present study was carried out to analyze the differences in the activity of ultimobranchial gland (UBG) between male and female fresh water teleost Mastacembelus armatus during reproductive cycle. Considerable variations in the nuclear diameter of UBG cells and plasma calcitonin (CT) levels during different reproductive phases of testicular and ovarian cycle suggested that the activity of the UBG depends upon the sexual maturity of fishes. A positive correlation was observed between plasma CT and sex steroid levels and the gonadosomatic index in both sexes which further confirmed the involvement of UBG in the processes related to gonadal development in fishes irrespective of the sex. Sudden increase in the level of plasma CT and nuclear diameter of UBG cells after administration of 17 α-methyltestosterone in males and 17 ß-estradiol in females during resting phase of the reproductive cycle clearly showed that UBG becomes hyperactive with increases in the level of sex steroids. Plasma calcium level was also found to be positively correlated with gonadal maturation in females. However no such change in plasma calcium level in relation to testicular cycle was observed. Thus it can be concluded that UBG becomes hyperactive during gonadal maturation but its role differs between male and female fishes. In females it may involved in both gonadal maturation and plasma calcium regulation while in males its involvement in calcium regulation was not justified. Variations in the level of CT during various phases of testicular cycle evidenced its involvement in gonadal maturation only.

[Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid gland].

The paper characterizes sclerosing mucoepidermoid carcinoma with eosinophilia, a rare thyroid tumor, including histological and immunohistochemical features. The authors give their observation of a 26-year-old patient. The immunohistochemical findings (positive p63 and TTF-1 tumor cell nuclear staining) show the dual nature of a tumor arising from the cells of the ultimobranchial body and follicular epithelium.

Hes1 is required for the development of pharyngeal organs and survival of neural crest-derived mesenchymal cells in pharyngeal arches.

Hes genes are required to maintain diverse progenitor cell populations during embryonic development. Loss of Hes1 results in a spectrum of malformations of pharyngeal endoderm-derived organs, including the ultimobranchial body (progenitor of C cells), parathyroid, thymus and thyroid glands, together with highly penetrant C-cell aplasia (81%) and parathyroid aplasia (28%). The hypoplastic parathyroid and thymus are mostly located around the pharyngeal cavity, even at embryonic day (E) 15.5 to E18.5, indicating the failure of migration of the organs. To clarify the relationship between these phenotypes and neural crest cells, we examine fate mapping of neural crest cells colonized in pharyngeal arches in Hes1 null mutants by using the Wnt1-Cre/R26R reporter system. In null mutants, the number of neural crest cells labeled by X-gal staining is markedly decreased in the pharyngeal mesenchyme at E12.5 when the primordia of the thymus, parathyroid and ultimobranchial body migrate toward their destinations. Furthermore, phospho-Histone-H3-positive proliferating cells are reduced in number in the pharyngeal mesenchyme at this stage. Our data indicate that the development of pharyngeal organs and survival of neural-crest-derived mesenchyme in pharyngeal arches are critically dependent on Hes1. We propose that the defective survival of neural-crest-derived mesenchymal cells in pharyngeal arches directly or indirectly leads to deficiencies of pharyngeal organs.

Postnatal fate of the ultimobranchial remnants in the rat thyroid gland.

The ultimobranchial follicles (UBFs) are considered embryonic remnants from the ultimobranchial body (UBB). They are follicular structures that vary in size and appearance depending on the age of the rat. The main objective of this article was to study the progressive changes in shape, size, and frequency of the UBFs in the postnatal rat, from birth to old-age. To accomplish that objective, a systematic morphometric and incidental study of the UBF has been carried out in 110 Wistar rats of different ages and both sexes, divided into three groups: 1) young rats (5-90-day-old); 2) adult rats (6-15-month-old), and 3) old rats (18-24-month-old). The glands were serially sectioned and immunostained for calcitonin at five equidistant levels. According to our results, UBFs were observed in all thyroid glands but a more exhaustive sampling was occasionally necessary in male rats. In young rats, immature UBFs predominantly appeared whereas in adult rats, mature UBFs with cystic appearance and variable luminal content prevailed. We frequently found spontaneous anomalous UBFs in old rats, which we have termed as "ultimobranchial cystadenomata." Additionally, in young rats, UBF areas significantly increased with age and they were larger when compared to that of normal thyroid follicles. Likewise, in adult rats, UBFs were significantly larger than normal thyroid follicles but only in female rats. In general, UBFs in females were also significantly larger than those found in male rats. Finally, all these differences related to UBFs together with a higher incidence in females of UB cystadenomata suggest a sexual dimorphism in regard to the destiny of these embryonic remnants during postnatal thyroid development.