Paper - Embryology of the parathyroid glands, the thymus and certain associated rudiments
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Gilmour JR. Embryology of the parathyroid glands, the thymus and certain associated rudiments. (1937) J. Path. and Bact. 45(3): 507–522.
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- 1 Embryology of the Parathyroid Glands, the Thymus and certain Associated Rudiments
- 1.1 Introduction
- 1.2 Material
- 1.3 I. The development of the parathyroid glands and thymus
- 1.4 II. The histology of the parathyroid glands
- 1.5 III. The number of parathyroid glands
- 1.6 IV. The size of the parathyroid glands at diﬁerent stages of development of the foetus
- 1.7 V. Rudiments
- 1.8 Summary
- 1.9 References
Embryology of the Parathyroid Glands, the Thymus and certain Associated Rudiments
J. R. Gilmour,
Grocers’ Research Scholar.
From the Bernhard Baron Institute of Pathology of the London Hospital.
(Plates LXIX — LXXII)
THE development of the parathyroids is intimately connected with that of the thymus, as is illustrated by the occurrence of parathyroids embedded in the surface of the thymus or buried Within its substance. The various positions in which the parathyroids may be expected to be found after birth are correlated with variations in the positions which the thymus ultimately comes to occupy. Further, the exact nature of various rudimentary structures which may be found in the neighbourhood of the parathyroids and thymus can only be determined by a study of the embryology of both and of adjacent embryonic ectodermal structures. The present study also gives What I believe to be the true origin and development of a portion of the thymus (thymus IV) which is sometimes found as a separate body of variable size within the thyroid or upon its posterior border on one or both sides. This body has the corresponding parathyroid (parathyroid IV) frequently embedded in its surface and occasionally buried Within its substance.
The nomenclature used in this paper is that of Grosser (1912). Glands derived from pharyngeal, or branchial, pouches are given the number of the pouch of origin. Thus parathyroids and portions of thymus derived from pouch III or pouch IV are called respectively parathyroid and thymus III or IV. The development of the parathyroids and the lobes of the thymus is bilateral. For brevity, therefore, structures present upon both right and left sides are given in the singular; thus thymus III or IV refers to this gland upon both sides unless a particular side is mentioned. The material examined was human and the observations recorded by others also concern only human material unless another animal is speciﬁcally mentioned. The age of the embryos and foetuses examined is derived from the tables of Mall (1910). As is shown in the following list the embryos and foetuses Were measured, from crown to rump, in the fresh state except, unfortunately, three embryos whose length from crown to rump had to be measured by serial section after they had been embedded in paraffin and were consequently reduced in size. The detailed ﬁndings in individual cases are given in an unpublished appendix, the typescript of which has been deposited in the General Library, British Museum (Natural Hsitory), London, S.W. 7.
The following embryos and foetuses were ﬁxed in 4 per cent. saline formaldehyde, embedded whole or in part in parafﬁn and cut in serial sections. Embryos (1) to (8) were embedded whole and cut in horizontal sections. In embryo (10) the right side of the neck and thorax was cut in sagittal sections. In embryo (9) and the six foetuses the neck and upper part of the thorax were cut in horizontal sections. The thickness of the serial sections and the intervals between those stained are given below. The sections were stained with haematoxylin and eosin.
(1) 3 mm. (measured by serial section), age 4-5 Weeks, 28 somatic segments, every section mounted.
(2) 7-1 mm. (measured by serial section), age 5-6 Weeks, every section at 10 )1. mounted.
(3) 16-5 m., age end of 6th week, every section mounted.
(4) 18 mm. A, S.D. 2770/35, age 7 weeks, every third section at 4 p mounted.
(5) 18 mm. B, S.D. 2551/36, age 7 weeks, every section at 7 p, mounted.
(6) 19-5 mm., S.D. 2875/36, age 7-8 Weeks, every other section at 7 ,1, mounted.
(7) 28 mm., S.D. 2672/36, age 9-10 weeks, every section at 7 /L mounted.
(8) 32 mm. (measured by serial section), age 9-10 Weeks, every section at 7 ,1, mounted.
(9) 35 mm., S.D. 771/34, age 9-10 Weeks, every ﬁfth section at 6 /1. mounted.
(10) Embryo, 9th-10th week, no measurement recorded, sagittal sections at 15 9, of right side of neck and thorax.
(11) 65 mm., S.D. 899/36, age 12-13 Weeks, every fourth section at 7 p, mounted.
(12) 76 mm., S.D. 2544/36, age 12-13 weeks, every fourth section at 7 I], mounted.
(13) 120 mm., S.D. 2573/36, age 16 Weeks, every fourth section at 7 /4. mounted. ‘
(14) 125 mm._. S.D. 2620/36, age 16 weeks, every fourth section at 7 p. mounted.
(15) 170 mm., S.D. 2210/36, age 20 weeks, every fourth section at 5 ,¢ mounted.
(16) 190 mm., S.D. 2492/36, age 22 weeks, every fourth section at 5 ,4, mounted.
I. The development of the parathyroid glands and thymus
Parathyroid III and thymus III. In the 3 mm. embryo there is no trace of these structures. In the 7-1 mm. embryo they are well developed; The absence of material between these stages makes it impossible to give their exact sites of origin from the pouch. In the 3 mm. embryo the third pharyngeal pouch is very small; it communicates with the pharynx by a Wide oriﬁce and is almost hemispherical. In the 7-1 mm. embryo the part of the pouch next the pharynx, that is to say the mesial part, has become a narrow, relatively short tube known as the ductus pharyngobrachialis III. This leads horizontally outwards from the pharynx to the lateral part of the pouch, which is much larger and longer and is directed caudalwards (ﬁg. 1). For convenience in description the term pouch may now be conﬁned to this part beyond the ductus pharyngobrachialis. The lateral and ventral wall of the pouch is replaced by a mass of water—clear cells, constituting parathyroid III (ﬁg. 2). A thickening of the dorsal wall of the cephalic half of the pouch bulges into the pouch, making the lumen a crescentic slit (ﬁgs. 1 B and 2). The pouch wall extends caudalwards for a short distance beyond the parathyroid and from its ventral part thymus III extends caudalwards as a tube (ﬁg.1 A). It is convenient to follow Kingsbury (1914-15, 1915) in calling the pouch (beyond the ductus pharyngobrachialis) together with its parathyroid and thymic derivatives a pouch-complex. At this stage, therefore, the complex lies at a little distance from the pharynx and is connected with it by a ductus pharyngobrachialis. In the 16-5 mm. embryo the ductus pharyngobrachialis III has disappeared, so that in this and older embryos pouch-complex III is completely separated from the pharynx. Parathyroid III occupies predominantly the lateral part of the hollow remnant of pouch. It has increased in bulk to form a rounded mass and with the remnant of the wall of the pouch on its mesial side it forms a “head” to the complex. The portion of pouch wall intercalated in the 7-1 mm. embryo between parathyroid and thymus has disappeared and the tubular thymus extends caudalwards directly from the “ head.” The wall of the thymic tube is thickened, the thickening increasing caudalwards, so that the thymus forms in the complex a “body” which expands from a “neck” where it is united to the “head.” In the 16-5 mm. and 18 mm. A embryos the upper half of the thymus is still tubular ; in the 18 mm. B embryo a little more than the upper half is tubular. Into the tubular upper part of the thymus a thickening of the dorsal wall bulges so as to make the lumen a crescentic slit. In the 16-5 mm. and two 18 mm. embryos parathyroid III lies just lateral, or cephalic and lateral, to the bifurcation of the carotid artery, and in the 16-5 mm. and 18 mm. A embryos it projects into a thin-walled vein, the future internal jugular. Thymus III extends down the outer border of the common carotid artery and the thyroid. After this stage the more rapid growth of the neck of the embryo than of thymus III and the greater development in bulk of the caudal part of the thymus cause the cephalic part of the thymus to descend relatively to the thyroid and to drag the attached parathyroid III with it. In the 19-5 mm. embryo the two parathyroids III have in this Way come for the ﬁrst time to lie caudal to the thyroid and to the parathyroids IV; they now occupy their permanent relative position as the lower parathyroids. In this embryo there is still a remnant of pouch wall and a slit—like lumen between it and the parathyroid. The pouch lumen is continued into a short remnant of tubular lumen in the cephalic end of the thymus. In the 28 mm. embryo and 65 mm. foetus the wall and lumen of the pouch have disappeared but there is still a remnant of tubular lumen in the upper part of the thymus (ﬁg. 3). In the other embryos over 28 mm. all these remnants are absent. During the descent caudalwards of the thymus its upper part becomes thinned to form the thymic cord of Hammar (1911). In the 19-5 mm. embryo this thymic cord makes its appearance. Later the cord either breaks, so that the thymus and parathyroid are separated, or it becomes transformed into thymic tissue and the two glands remain connected. When the thymic cord breaks it usually disappears rapidly. The cord is present and connects the thymus with the parathyroid on both sides in the 19-5 mm., 32 mm. and 9-10 weeks’ embryos, on the left side only in the 28 mm. and 35 mm. embryos. In the 9-10 weeks’ embryo the cord on the right side passes through the anterior border of the thyroid to reach the parathyroid. In the 65 mm. and ﬁve older foetuses the thymus is fused to the parathyroid directly, without the intervention of a cord, on both sides in one and on one side in one. In another a small accessory parathyroid gland is attached to the thymus while the main parathyroids are separated. The origin of such an accessory parathyroid is doubtless seen in the 65 mm. foetus, in which a small group of water-clear cells lies in the thymic end of the thymic cord (ﬁg. 4). In another foetus the parathyroid on one side is fused with a separate small mass of thymic tissue, the thymus lobule III of early German authors (ﬁg. 5). This lobule of thymus has presumably developed from the upper end of a cord which had separated near its caudal end.
FIG. 1.—Emb1-yo of 7-1 mm. Diagram of pharyngeal pouch-complexes III and IV ; pharynx and pouches, yellow; parathyroids, red; thymus, blue.
A. Ventral view, with windows cut through ventral surface. Par. III and IV, parathyroids III and IV ; Th. III and IV, thymus III and IV. Thymus III is shortened by one-third ; lower third passes caudalwards ventral to D.P. IV. Ph., pharynx; D.P. III and IV, ductus pharyngobrachialis III and IV. Ect., ectoderm; V., vesicula, eervicalis; D.C., ductus cervicalis, outlined to indicate relations to complex III.
B. Horizontal sections through complexes III and IV.
Ectodermal structures in relation to the third pouch.
In the 3 mm. embryo, pharyngeal pouch III communicates directly with the external surface through a duct of ectodermal origin—the ductus cervicalia. This is joined by a duct from pouch II—the ductus brachialis II—so that this pouch also communicates with the outside. Further, a branch of the ductus cervica1is—the ductus brachialis IV—reaches but does not communicate with pouch IV. In the 7-1 mm. embryo (ﬁg. 1) the ductus brachialis II and ductus brachialis IV are no longer recognisable. The ductus cervicalis communicates with the outside by a wide oriﬁce, while its inner part is expanded to form a. vesicula cervicalts which lies dorsal to and against the caudal part of the third pouch—complex but does not communicate with either the third, second or fourth pouch. It extends ‘somewhat caudalwards, however, towards the fourth pouch.
In the 16.5 mm. embryo and the two 18 mm. embryos the ductus cervicalis has disappeared but a very small Vesicula cervicalis lies upon the ventral surface of the vagus ganglion. It is joined to the remnant of the third pharyngeal pouch in pouchcomplex III near the large dorsal limb of its crescentic lumen, but its cavity does not communicate with that of the pouch. In the 18 mm. A embryo the Vesicula is full of red blood corpuscles. In the 19-5 mm. embryo a minute Vesicula is present. It is attached to but does not communicate with the remnant of branchial pouch III, which is now very small. The Vesicula in this embryo has descended with complex III below the thyroid. On one side it is full of red corpuscles. In later embryos no remnant of the Vesicula is seen. Parathyroid I V and thymus IV. In the 3 mm. embryo there is no trace of parathyroid IV or thymus IV. A bay projects caudalwards from the fourth pouch and reaches the pericardium, but the epithelium resembles that of the rest of the pouch and the communication with the pouch is too wide for a thymic diverticulum. In the 7-1 mm. embryo parathyroid and thymus IV are seen for the ﬁrst time. In general appearance pouch IV with its derivatives resembles closely pouch III (ﬁg. 1). A ductus pharyngobrachialis IV, shorter and wider than the ductus pharyngobrachialis III, connects the pouch—complex to the pharynx. In the pouch-complex parathyroid IV is a solid mass of water—clear cells occupying the lat-eral wall of the pouch. By its growth it has widened the lateral extremity of the pouch and has bulged into the lumen, thus expanding the lumen into narrow dorsal and ventral diverticula (fig. 1 B). Thymus IV is a tubular diverticulum which arises from the caudal extremity of the pouch and passes caudalwards, inwards and slightly Ventralwards. In the l6.5 mm. embryo, pouchcomplex IV consists of parathyroid IV, a portion of the original pouch wall and, caudal to these, a tube-like thymus. It is still connected with the pharynx by the ductus pharyngobrachialis IV, which is now long and very narrow. In this persistence of the ductus pharyngobrachialis and absence of proliferative thickening of the wall of the thymus it differs from pouch-complex III in the same embryo.
In the two 18 mm. and later embryos the ductus pharyngobrachialis has disappeared, so that the pouch-complex lies free from the pharynx. In the 18 mm. A embryo the thymus passes caudalwards from a hollow structure which rests upon the ventral surface of‘ the parathyroid and appears to be a remnant of the pouch ; it is not possible, however, to prove that this structure is not the cephalic extremity of the thymus. If this structure is accepted as a remnant of pouch then complex IV is very like complex III : it is free from the pharynx, has a “ head ” formed by the parathyroid and the remnant of pouch wall, and a “neck ” where this remnant is continued caudalwards by a thymus that expands rapidly to form a “ body.” In the 18 mm. B and 19-5 mm. embryos there is no remnant of pouch, although a lumen is still present in thymus IV. The remnant of original pouch disappears, therefore, slightly earlier in complex IV than in complex III. Further, in the two 18 mm. embryos and the 19-5 mm. embryo the shape of the thymus differs from that of thymus III; the thymus is shorter and somewhat rounded and it has a tortuous lumen. Reduction in length of the thymic lumen, ending in its disappearance, progresses slightly more rapidly in thymus IV than thymus III. Thymus IV is still completely tubular in the 18 mm. A embryo ; the lumen is very short in the 18 mm. B and 195 mm. embryos and is absent in the 28 mm. embryo. In the two 18 mm. embryos parathyroid IV has come to occupy its permanentposition, dorsal to the thyroid. Thymus IV is now also dorsal to the thyroid and touches it. In the two 18 mm. embryos a very small area of thymus IV is fused with the dorsal surface of the thyroid; in the 19-5 mm. and 28 mm. embryos a large area is fused with the thyroid trabeculae, which have grown round the thymus to enclose all save its dorsal and medial surfaces. In the 165 mm., 18 mm. A and 19-5 mm. embryos the parathyroid and thymus are still united, but in the 18 mm. B and 28 mm. embryos the two structures have separated upon both sides. Separation of the parathyroid from the thymus is, therefore, in general earlier in complex IV than complex III. Thymus IV is identical histo— logically with thymus III in embryos up to 18 mm. long. In the 19-5 mm. embryo it is stained slightly darker than thymus III. In the 28 mm. embryo its cells have become stellate and form a reticulum and some of their nuclei are shrunken and pyknotic. A reticular arrangement of the cells is seen in thymus III, when it is becoming transformed into thymio tissue. Owing, however, to the shrinkage and pyknosis of nuclei here it is not possible to decide whether this change initiates the differentiation of the body into thymio tissue or its disappearance.
Thymus IV is seen in only one of the nine embryos and foetuses over 28 mm. in length, that is in 11 per cent. It is present in the 120 mm. foetus. It is bilateral and has differentiated into thymio tissue with cortex and medulla. On one side it is still fused with parathyroid IV, which lies dorsal to but free from the thyroid. On the other side it is free from the parathyroid and lies entirely within the thyroid (ﬁg. 6). A small accessory parathyroid and a paraganglion are also included within the thyroid on this side. Another instance of inclusion of thymus IV within the thyroid was seen recently in an infant aged two days.
A small mass (0.45 by 0.25 cm.) of white lobulated thymus lay in the middle of the right lobe of the thyroid, reaching to 0-2 cm. from its surface (ﬁg. 7). Serial sections show that it has cortex, medulla and I-Iassall’s corpuscles and is distinctly separated everywhere from the thyroid tissue. Also inside the thyroid, 400 y, from the thymus, is a hollow structure, 300 y. in greatest length. It is lined with many layers of squamous cells and towards the lumen a layer of more columnar cells, some of which are ciliated. The nature of this structure is doubtful but it is probably thyroglossal in origin. The right upper parathyroid (parathyroid IV) lay outside the thyroid. It contains some paraganglionic tissue in its hilum.
In 20 dissections of new—born infants and infants up to one day old persistence of thymus IV on one or both sides (3 unilateral, 2 bilateral) was found in 5 or 25 per cent. The thymus was always dorsal to and separate from the middle of the posterior border of the thyroid, was of about the size of a pea and had the same appearance as thymus III. Parathyroid IV frequently lay embedded in its surface. As a differentiated thymus IV was found in 1 out of 9 embryos and foetuses over 28 mm. in length and in 5 out of 20 new—b0rn infants and infants up to 1 day old, its incidence in the total series is approximately 21 per cent.
Parathyroid III and thymus III. It is generally agreed that parathyroid III and the main mass of the thymus (thymus III) come from the third branchial pouch, and the description given above of the development of parathyroid III and thymus III agrees in general with the view now held by other authors. Owing to the gap in the material between the 3 mm. and 7 -1 mm. embryos the exact site of origin of the parathyroid and thymus from the third branchial pouch was missed. It is generally agreed that parathyroid III arises from the dorsal and thymus III from the ventral wall of the pouch. In the 7-1 mm. embryo thymus III extended from the caudal and Ventral part of the pouch but parathyroid III occupied its lateral and ventral wall. Hammar described a rotation of the pouch—complex by which parathyroid III, originally on the dorsal wall of the pouch, comes to present ventrally. The rotation is due to the continued growth of the neck of the embryo. Comparisons are given below between the ages at which various changes were seen in the present material and in that of others. Unfortunately the comparison loses value because the other authors do not state whether the length of their embryos was measured before or after ﬁxation and embedding.
There is no trace of thymus III and parathyroid III in the 3 mm. embryo measured after embedding. Hammar saw thymus III in a 3 mm. embryo but not in one of 3-4 mm. which was of younger age according to the development of the organs. Both parathyroid III and thymus III are Well developed in the 7-1 mm. embryo measured after embedding; Kingsbury (1915) saw parathyroid III in a 7-5 mm. embryo but Grosser (1912) could not see any parathyroids in an 11 mm. embryo. The ductus pharyngebrachialis III had disappeared in the 16-5 mm. embryo ; it ﬁrst disappeared in 14 mm. embryos of Tourneux and Verdun (1897) and Grosser (1912), and in 14-5 mm. embryos of Hammar (1911) and Weller (1933), but it was still present upon one side in an abnormal 18-5 mm. embryo of Hammar. The projection of a thickening of the dorsal wall of the upper tubular part of the thymus so as to make the lumen crescentic was seen in the 16-5 and 18 mm. A embryos; Hammar after describing an 11-7 and a 17 mm. embryo said that this thickening appeared about that time. Parathyroid III had come to lie caudal to parathyroid IV in the 19-5 mm. embryo ; this had occurred in a 15-4 mm. embryo of Hammar and a 16 mm. embryo of Tourneux and Verdun. The thymic cord was ﬁrst seen in the 19-5 mm. embryo ; Hammar saw it ﬁrst in a 21 mm. embryo. A remnant of the lumen and wall of the branchial pouch was last seen in the 19-5 mm. embryo ; I-Iammar saw similar remnants in the neck of the complex in his 20, 20-5, 21, 21-1 and 22-3 mm. embryos, but he thought that the hollow remnant might possibly be a remnant of the vesicula cervicalis. The thymic cord was absent on one side in the 28 and 35 mm. embryos, and on both sides in the 76 mm. and four older foetuses; Hammar saw unilateral disappearance of the cord in 30-5 and 51 mm. embryos and a 70 mm. foetus, and at least in part on both sides in 33-4, 36-8 and 52 mm. embryos and 65 and 85 mm. foetuses. Kingsbury (1915) saw the cord ﬁrst ruptured in a 35 mm. embryo. As in my 9-10 weeks’ embryo the thymus with a parathyroid in its tip was seen by Kiirsteiner (1898-99) to pass through the thyroid in a 220 mm. foetus.
Parathyroid IV and thymus I V. The description given above of the development of the derivatives of the fourth pouch agrees with the generally accepted view so far as parathyroid IV is concerned. It differs markedly, however, in respect of the structure called thymus IV in the embryos between 7-1 and 28 mm. This structure, as the name implies, is described as the precursor of the portion of differentiated thymus which is found in a certain number of foetuses and adults and which has been called in the literature thymus IV because of its close relationship to parathyroid IV. All other authors call this structure in early embryos either the ultimobranchial, postbranchial or lateral thyroid body and with the exception of Stewart (1918), who studied cats, consider that it plays no part in the development of thymus IV. Almost all authors, for instance Born (1883), Tourneux and Verdun (1897), Grosser (1910, 1912) and Kingsbury (1914-15, 1915), believe that this ultimobranchial or lateral thyroid body disappears after fusion with the thyroid, but a few, for instance Weller (1933), state that it takes part in the formation of thyroid tissue.
Apart from the difference in the interpretation of the signiﬁcance and consequently in the nomenclature of the structure in the fourth pouch-complex, which is called here thymus IV and by others the ultimobranchial, postbranchial or lateral thyroid body, the description given of the development of the pouch—comp1ex resembles that given by other authors, as is shown by the following comparison. In this the term thymus IV is used for the rudiment in dispute when seen in my material.
Parathyroid IV is stated by all authors to arise from the dorsal wall of the fourth pouch. It was not seen in the 3 mm. embryo, but was well developed in the 7-1 mm. embryo, measured after embedding. It replaced the lateral wall of pouch IV. Kingsbury (1915) did not ﬁnd it in a 7-5 mm. embryo although parathyroid III was present. Tourneux and Verdun saw it in an 8 mm. and Hammar in an 8-3 mm. embryo. Thymus IV was ﬁrst seen in the 7 -1 mm. embryo. Hammar saw the lateral thyroid Amlagc in a 5 mm. embryo. In the 7-1 mm. embryo thymus IV was a diverticulum from the caudal part of pouch IV. All authors agree that the ultimobranchial, postbranchial or lateral thyroid body arises from the caudal part of the fourth pouch or, as some prefer to call it, a rudimentary ﬁfth pouch. No evidence was found in the 3 mm. and 7-1 mm. embryos in support of the contention that the caudal part of the fourth pouch is a rudimentary ﬁfth. The ductus pharyngobrachialis IV was still present in the 16-5 mm. embryo but absent in the two 18 mm. and later embryos. It ﬁrst disappeared in a 13 mm. embryo of Weller and in a 14-5 mm. embryo of Kingsbury (1914-15), but it was still present in a 16 mm. embryo of Weller. Thymus IV was completely tubular in the 18 mm. A embryo, but the lumen was very short in the 18 mm. B and 19-5 mm. embryos and had disappeared in the 28 mm. embryo. Tourneux and Verdun (1897) and Grosser (1912) found no lumen in the lateral thyroid or ultimobranchial body in a 16 mm. and a 19-75 mm. embryo, while Kingsbury (1914-15) saw it in two 19 mm. embryos and said that it was ultimately lost. In the two 18 mm., the 19-5 mm. and the 28 mm. embryos part of the surface of thymus IV was fused with the thyroid. Weller saw the lateral thyroid body fused with the thyroid in a 13 mm. embryo and Kingsbury ( 1914-15) noted similar fusion of the ultimobranchial body in embryos of 12, 13-5 and 15 mm. but not in others of 13-6 and 14-5 mm. The stellate shape and reticular arrangement of the cells of thymus IV seen in the 28 mm. embryo was observed by Kingsbury in the ultimobranchial body after its fusion with the thyroid. The rudimentary thymus IV was last seen in the 28 mm. embryo, a differentiated thymus IV being found in the 120 mm. foetus among the nine embryos and foetuses over 28 mm. in length. Kingsbury (1914-15) last saw the ultimobranchial body deﬁnitely recognisable in a 25 mm. embryo, and Grosser (1910) failed to ﬁnd it in a 27 mm. and older embryos. A differentiated thymus IV was found in the present series either within or outside the thyroid. In the 120 mm. foetus it lay free from the thyroid on one side and buried within the thyroid on the other. It was buried within the thyroid on one side in an infant aged two days, and lay outside the thyroid on one or both sides in 5 out of 20 newborn infants and infants up to one day old. Kingsbury (1914-15) in his embryos 25-41 mm. in length saw a condensation in the thyroid, which he ascribed to the ultimobranchial body, and in a 37 mm. embryo saw this condensation connected with parathyroid IV by an epithelial vesicle. This condensation must not be confused with the area of increased cellularity in the centre of the thyroid, presumably an area of more active growth, described by Grosser (1910) ; this area of increased cellularity was seen in the thyroids of some of the embryos in the present series. In a 32 mm. embryo Kingsbury (1934-35) saw a lack of inclusion of the ultimobranchial body within the thyroid and absence of a reticular arrangement, and pyknosis of its cells. He encountered a number of similar instances of persistence of a portion of the body outside the thyroid.
According, therefore, to the accepted view the structure known as the ultimobranchial, postbranchial or lateral thyroid body plays no part in the formation of thymus IV. Stewart alone, working upon cats, states that all, or all that persists, of the ultimobranchial body is transformed into thymus IV. His view, therefore, coincides with that given in this paper except that he retains the term ultimobranchial body for the stages before differentiation. A few authors have not recognised the existence of thymus tissue derived from the fourth pouch. Kiirsteiner saw thymus tissue connected with parathyroid IV in foetuses but did not in consequence deduce its origin from pouch IV. Weller, in a recent extensive work upon the embryology of the derivatives of the pharyngeal pouches, makes no mention of thymus IV. Most authors, however, following Herrmann and Verdun (1899) and Groschuff (1896), have given the differentiated thymus IV this name because they consider that it must be derived from pouch IV. They consider that it has some origin from pouch IV separate from the ultimobranchial, postbranchial or lateral thyroid body. The only claims, however, to have seen anything of this separate development have been made by Groschuff (1896) in animals and Tandler (1909) in man, and they only describe what they believe on theoretical grounds to be its earliest rudiment. They observed a ventral diverticulum from pouch IV and considered this to be the Anlage of thymus IV because thymus III arises from a ventral diverticulum of pouch III. A small ventral diverticulum is certainly formed in the fourth pouch. Kingsbury (1914-15) saw it in a 7 mm. embryo but said that it later became absorbed into complex IV and was not observed in embryos longer than 10 mm. In the 7-1 mm. embryo in the present series this ventral and also a dorsal diverticulum have been described above, and both diverticula have been attributed merely to the thrust of the enlarged parathyroid IV into the lateral extremity of the pouch. It has been shown above that a differentiated thymus IV is found in about 21 per cent. of foetuses and infants up to 1 day old. If, therefore, it is not derived from the structure known as the ultimobranchial, postbranchial or lateral thyroid body, it is difficult to understand how no more of its development than the transient diverticulum of Groschuif and Tandler should have been seen by so many careful observers.
The evidence is overwhelming that the so-called ultimobranchial, postbranchial or lateral thyroid body is in reality thymus IV. Thymus III and the ultimobranchial body both appear before the corresponding parathyroids. According to other authors thymus III differs at its inception from the ultimobranchial body in that it arises from the ventral wall of the third pouch While the ultimobranchial body (thymus IV) arises from the caudal wall of the fourth. When, however, the third pouch has been rotated owing to the growth in length of the neck of the embryo (Hammar), both diverticula occupy a similar position, as is seen in the 7-1 mm. embryo (ﬁg. 1). The development of the two complexes in the 7-1 to 28 mm. embryos is essentially similar. Certain differences have been pointed out in the descriptions of the development of pouchcomplexes III and IV but these differences are slight variations in gross form and in time relations. The signiﬁcance of the slight variation in time relations when the two complexes are compared is further reduced by these time relations being inconstant in both complexes when considered separately. The resemblances are obviously much greater than the differences. Thymus IV (the ultimobranchial body) is identical histologically with thymus III in the embryos up to 18 mm. long and differs only in being more deeply stained in the 19-5 mm. embryo. In the 28 mm. embryo its cells have a reticular arrangement such as is seen in thymus III when it is becoming differentiated into thymic tissue. The differences in the staining, of the cells and their nuclei seen in these later embryos are probably connected with the disappearance of thymus IV which undoubtedly occurs in some 79 per cent. of subjects. When thymus IV persists and is differentiated it is found sometimes within the thyroid but more often outside. Before its disappearance, the ultimo—branchial body either becomes included within the thyroid or remains outside the thyroid (Kingsbury, 1914-15, 1934-35).
The fact that thymus III and the ultimobranchial body (thymus IV) are believed to arise from different parts of the walls of pouches III and IV may have prevented authors from considering the two structures to be homologous, but there can be little doubt that the main reason why authors, with the exception of Stewart, have not recognised that the ultimobranchial, postbranchial or lateral thyroid body is the precursor of thymus IV is that the former structure had been described and accepted in the literature before the differentiated thymus IV had been discovered.
II. The histology of the parathyroid glands
From their ﬁrst appearance in the 7-1 mm. embryo the glands are rounded solid masses of characteristic cells. The cells are small and water-clear, with conspicuous cell-membranes (ﬁg. 2). They are usually polygonal but in a layer round the periphery of the gland or upon capillaries or any ﬁbrous stroma they are sometimes short columnar and arranged as a palisade, their nuclei lying in the cytoplasm furthest from the periphery of the gland or the capillaries or ﬁbrous stroma. One or two delicate capillaries are already present in the 16-5 mm. embryo. In the 190 mm. foetus a little connective tissue separates some of the vessels from the cells of the parenchyma. A very delicate capsule composed of one or two layers of spindle cells and delicate ﬁbres appears almost as soon as the glands are formed. In some foetuses a zone of tissue composed of somewhat concentrically arranged small spindle cells and rareﬁed by wide spaces surrounds the parathyroids, especially the lower parathyroids, and their associated thymus. It lies outside the capsules of these glands. Before the parathyroid and thymus have separated it encloses both together (ﬁg. 3). After they have separated it may invest each separately. In two fwtuses special stains were applied and showed that there is more mucus i11 this zone than in the other connective tissues. These zones of rareﬁed tissue are known as thymic ﬁelds of Kiirsteiner and probably represent the beginning of cleavage in the tissues.
There is a little heemopoiesis in the parathyroid glands of ‘a few of the foetuses. In the 19-5 mm. embryo a megakaryocyte lies in a capillary in one gland. In the 125 mm. foetus a little leucopoiesis surrounds vessels in places. In the 190 mm. foetus a little focal intra- and extravascular erythropoiesis and less leucopoiesis and one intraoapillary megakaryocyte are present.
III. The number of parathyroid glands
In 14 of the 16 specimens parathyroids had developed and the total parathyroid-bearing area had been examined. Four glands are present in all 14 and in 3 there are accessory glands. In the 65 mm. foetus an accessory lower gland lies between the two main lower glands slightly to the left of the midline, while a small mass of water—clear cells forms the germ of a second accessory lower gland in the left thymic cord (ﬁg. 4). In the 120 mm. foetus an accessory upper gland lies deep within the left lobe of the thyroid (ﬁg. 6). In the 125 mm. foetus an accessory left lower gland is attached to the upper pole of the left lobe of the thymus in front of the isthmus of the thyroid, while an accessory right lower gland lies in front of the right lobe of the thyroid and is free from the thymus.
IV. The size of the parathyroid glands at diﬁerent stages of development of the foetus
The size of the glands in the different embryos and foetuses is given in the following table.
It can be seen that in at least 8 of the 13 specimens parathyroid III is larger than parathyroid IV.
FIG. 2.—Embryo, 7'1 mm. Parathyroid of waterzclear cells in ventral and lateral Wall of pouch-complex III. Hzaem. X 420.
FIG. 3.—Fcetus, 65 mm. Lower parathyroid and upper part of thymic cord,with persistent lumen, enclosed in 9. Kﬁrsteiner thymic ﬁeld. Haem. and eosin. X 77.
FIG. 4.—Foetus, 65 mm. Thymus and thymic cord. A, area. of water-clear cells, germ of accessory parathyroid, in cord; B, solid cellular bud from cord; 0, two isolated solid cellular masses. Haem. and eosin.
FIG. 5- Foetus 190 mm- A, Parathyroid
FIG. 6.—Foetus, 120 mm. Thyrnus IV Within fused with B, thymus lobule III; C, vesicle and fused with thyroid. Accessory upper Of type 3; D, group of glandular alveoli of parathyroid (oval mass of water—clear cells) type 3: Opefling into vesicle of type 3; E, within thyroid to right of thymus. Harem. thymus III. Harm. and eosin. X40. and eosin. x 150.
F10. 7.—I,v.1fant aged 2 days. Thymus IV Within FIG. 8.~—Foetus, 190 mm. Cord of thyroid. Haem, and eosin. X 8. water-clear cells passing from the lower parathyroid containing vesicles of type 1 with colloidlike coagulmn. Haem. and eosin, x 132.
h roi mi . Length of specimen Calculated Pant y <1“ cm) (crown-rump). 389 (Weeks>‘ III. IV. Accessory. 18 mm. A. 7 l56)<l35><90 138Xl44XlO8 18 ,, B. 7 l85><l50><126 200><l70><l5O l9~5 ,, 7-8 224><150><138 2l0><120X98 23 ,, 9—10 160Xl20X1l4 l50><135X98 32 ,, 9-10 225><150><140 225><l70><140 I 35 ,, 9-10 l50Xl25><l10 l50Xll0><9O l 9-10 l70><l50><l35 l70><165><l50 65 mm. 12-13 230><l90><l68 168><l70><l20 (1) 63X63X56 I (2) 90 X 56 x 39 '73 ,, 12-13 300><203X200 200><200X175 ' 120 ,, 16 340 X 320 X 259 344 X 330 X 280 95 X 40 X 35 125 ,, 16 350><320><269 370><269X220 (1) 130><ll0X63 (2) 90 x 70 x 63 170 ,, 20 890 X 750 X 400 780 X 350 X 250 ... 190 ,, 22 830 X 700 X 685 750 X 650 X 620
Vesicular, canalicular and gland—like structures derived from the parathyroid, thymus or thymic cord are found in the foetuses. They can be collectively called canals of Kiirsteiner (1898-99), since this author gave some description of them. They are rudimentary and of no apparent function but are important in that they persist into adult life and must be recognised if cystic structures in the neighbourhood of the parathyroids after birth are to be interpreted correctly. All were found in association with parathyroid III and thymus III. They show considerable morphological variation. Three types can be distinguished, although transitions occur between these. Type 1. On the surface of lower parathyroid glands (para thyroid III), usually the ventral surface, small solid cellular buds are frequently seen. The cells are Water~clear and their nuclei are grouped near the centre of the bud, which is two cells wide in any diameter (ﬁg. 10). Some of the buds become separated from the gland. A lumen may be formed within the bud before or after separation, converting the bud into a vesicle (ﬁg. 9). The lumen usually contains a homogeneous eosinophil almost colloid—like secretion (ﬁg. 8). In the foetuses of 120 and 170 mm. a long process of Water-clear cells extends from the parathyroid to end in a vesicle ; in the 120 mm. foetus the vesicle contains eosinophil coagulum. In the 190 mm. foetus a similar cord lies along the ventral surface of a lower gland and contains several vesicles (ﬁg. 8). On the surface of each upper gland in the 125 mm. foetus a single solid bud of Water—clear cells was seen, similar to those so frequently seen upon the lower glands, but no Vesicular or canalicular structure was ever seen on or near the upper glands.
Structures of this type were seen in the 76, 120, 125, 170 and 190 mm. foetuses. They are evidently derived from parathyroid.
Type 2. Gland-like alveoli are occasionally seen with a small lumen surrounded by cubical cells which are not water—clear but have stained cytoplasm. In most the lumen contains mucus which is stained lightly by haematoxylin and metachromatically by toluidin blue. In the 125 mm. foetus a long canal extends from the lower parathyroid (ﬁg. 10). It has a few short lateral branches and so resembles a racemose gland. It is lined with cubical cells which are stained except at its free extremity, where they are water—clear. It contains an eosinophil colloid—like coagulum near its attachment and at its free extremity; elsewhere it contains a haematoxyphil mucoid coagulum. This canal is obviously of parathyroid origin and possibly arose from the cords of water—clear cells mentioned in the foetuses of 120 and 170 mm. in the description of type 1. The remaining gland—like structures lie free from the parathyroid. Some may have arisen from it, especially a tubular example which lies close to one gland in the 120 mm. foetus. Usually they are gathered into small groups which are unconnected with any other structure. These lie as a rule close to the parathyroid but sometimes are nearer the thymus. Occasionally one alveolus of the group is distended with secretion to form a small Vesicle. Sometimes one or two of the outermost alveoli in a group open into the larger vesicles of type 3 (ﬁg. 5). In the 170 mm. foetus a group of alveoli secreting mucus and containing granular brown pigment in their cells (ﬁg. 11) is seen behind a ﬂattened vesicle of type 3, which lies Ventral to the trachea. In the 190 mm. foetus also some of the cells of some alveoli contain a little pigment. This pigment is a characteristic of the gland—like groups of alveoli that have persisted into adult life. Structures of this type are seen in the 76, 120, 170 and 190 mm. foetuses. Their origin is doubtful, since only one was connected with the parathyroid. They probably arise also from the thymus or its cord.
Type 3. This type consists of larger vesicles or ﬂattened canals which are lined with stained (not water—clear) ﬂat cells and are empty or contain a few ﬂakes of mucus. They are often single (ﬁg. 5), but when of greatest development they form groups of intercommunicating vesicles (ﬁg. 12). They tend to lie close to the upper pole of the thymus (thymus III), and part of a single vesicle or group of vesicles is often attached to it. A mucus-secreting glandular alveolus or group of alveoli of type 2 occasionally opens into them.
The origin of the vesicles of this type can be traced to the thymic cord and thymus. On the surface of the thymic cord solid buds of stained cells (ﬁg. 4) are seen in the 32 mm. and 9-10 weeks’ embryos and the 65 mm. foetus. Some of these buds become free (ﬁg. 4), and even at an early age some are converted into vesicles before or after separation. A small vesicle is connected with the thymic cord in the 32 mm. embryo. Groups of small detached vesicles are seen in the 65 mm. foetus. From the surface of the thymus itself minute vesicles lined with stained, somewhat ﬂattened cells project already in the 28 mm. and 9-10 weeks’ embryos and the 76 mm. foetus, while similar vesicles are seen in the older foetuses, especially between thymic lobules. Continued growth and multiplication of these minute vesicles doubtless accounts for the larger examples of this type. Fully developed vesicles are present in the 76, 120, 125, 170 and 190 mm. foetuses.
FIG. 9.—Foetus, 76mm. Lower: parathyroid (P) fused with FIG. 1l.—F0etus, 170 mm. A, two separate lobules of thymus III ('1'). Vesicle (V) gland-like canal Of type 2; of Water-clear cells (type 1) budding from parathyroid. B, collapsed vesicle of type 3. Haem. and eosin. X 128. Haem. and eosin. X 94.
FIG. 10.—Foetus, 125 mm. Duct-like process, lined with FIG. l2.——Foetus, 122 mm. stained cubical cells (canal of type 2), extending from the Group of large vesicles of lower parathyroid. Solid bud (B) of Water-clear cells on type3close toupper part of parathyroid. Haem. and eosin. X95. thymus. Haem. and eosin.
No evidence was found that any of the structures of the above three types were derived from the ectodermal structures described above (p. 510) in relation to the third pharyngeal pouch, except probably a small vesicle of type 3 in the 19~5 mm. embryo. A Very small vesicula cervicalis is still visible in the 166 and 18 mm. embryos. It lies upon the ventral surface of the vagus ganglion close to the cephalic extremity of thymus III. It is joined to the remnant of the third pharyngeal pouch in p0uch—complex III but the two lumina do not communicate. In the 19-5 mm. embryo there is no longer any trace of the vesicula cervicalis in the region of the vagus ganglion or the bifurcation of the carotid artery, but at the cephalic extremity of complex III a small vesicle of type 3, lined with ﬂattened stained cells, is attached to but does not communicate with the tubular remnant of the original pouch. Inasmuch as this vesicle has the same relation to the remnant of pouch as the remnant of the vesicula cervicalis in the two earlier embryos of 16-5 and 18 mm., it was considered in the description given above to be a remnant of the vesicula cervicalis which had descended with the third pouch complex into the region caudal to the thyroid.
The development of the parathyroid glands and portions of the thymus from the third and fourth pharyngeal, or branchial, pouches in 16 human embryos and foetuses from 3 mm. to 190 mm. in length (crown to rump) is described and compared with the account given in the literature. Embryonic ectodermal structures in relation to the third pouch are also described.
It is contended that the structure hitherto called the ultimobranchial, postbranchial or lateral thyroid body is in reality thymus IV, being the early stage of the inconstantly differentiated and persistent thymus IV.
A differentiated thymus IV was found on one or both sides in 1 (a foetus of 120 mm.) out of 9 subjects of from 32 to 190 mm. in length and in 5 out of 20 new-born infants and infants up to 1 day old. In one foetus it was on one side buried Within the thyroid ; an instance is quoted of thymus IV in a similar position in an infant.
A table is given of the size of the parathyroid glands at different stages of development of the foetus.
In 14 of the 16 embryos and foetuses parathyroids were present and the Whole parathyroid—bearing area had been examined. Four glands were present in all 14, and in 3 one or two accessory glands were also found.
Three types of vesicular, canalioular or gland-like rudiments derived from the parathyroid, thymus or thymio cord are distinguished and described. They were all derived from the lower parathyroids (parathyroid III) or its associated portion of the thymus (thymus III).
I am greatly indebted to Professor H. M. Turnbull for help in the preparation of this paper.
BORN, G. . . . . . . . Arch. mikr. Anat., 1883, xxii. 271.
GROSCHUFF, K. . . . . . Anat. Anz., 1896, xii. 497. ,, . . . . . Ibid., 1900, xvii. 161.
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Weller GL. Development of the thyroid, parathyroid and thymus glands in man. (1933) Contrib. Embryol., Carnegie Inst. Wash. 24: 93-139.
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