Paper - The early morphogenesis of the human thyroid gland
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Norris EH. The early morphogenesis of the human thyroid gland. (1918) Amer. J Anat. 24(4): 443-
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The Early Morphogenesis of the Human Thyroid Gland
Edgar H. Norris
Institutc Of Anatomy, University Of Minnesota
The general facts regarding the derivation and early morphogenesis of the human thyroid gland (‘median thyroid’), having been repeatedly set forth by numerous investigators, are well known. Notwithstanding the multiplicity of these observations, however, certain important features have been overlooked. Furthermore, no systematic and complete arrangement of the developmental stages has been provided and our knowledge of them is at best somewhat fragmentary and scattered. This results primarily from the lack of adequate series of successive embryonic stages hitherto available for study. In the present paper, which is based upon the study of a large and complete series of_ young human embryos, an attempt has been made to formulate an interpretation of the processes involved in the development of the median thyroid, as well as to present certain original. observations.
This work, which suggested itself to the author during the course of an earlier investigation upon the morphogenesis of the thyroid follicles (Norris, ’16), has been carried on at the Carnegie Institute of Embryology and at the University of Minnesota under the supervision of Prof. C. M. Jackson. I wish to thank Dr. Jackson for his valuable aid and criticism. I Wish further to acknowledge my indebtedness to Dr. F. P. Mall for his kind assistance in providing a special grant for carrying on this study and for the many favors received While Working in his laboratory.
2. Materials and Methods
This study is based upon the collection of human embryos in the Carnegie Institute of Embryology at Baltimore and upon those in the Anatomical Laboratory of the University of Minnesota. The embryos have been variously ﬁxed and stained, and many of the series used are in excellent condition for histological study.
The accompanying table shows the material used in this work. The seVenty—two embryos used are arranged in order of their croWn—rump length. An asterisk (*) following the collection number signiﬁes that the specimen belongs in the collection of the University of Minnesota; the specimens which are not so marked are in the collection of the Carnegie Institute.
The ordinary reconstruction methods, both plastic (Born’s wax-plate method) and graphic, have been utilized. The drawings from sections for reconstructions and for teXt—ﬁgures were made with the camera lucida or With Edinger’s projection apparatus. MORPHOGENESIS 01+‘ HUMAN THYROID GLAND 445
Table of embryos studied
COLLECTION NUMBER 0. R. LENGTH
S ECTION THICKNESS
33 34 35 36 37 38 39 40 41 42
120113 2.0 391 2.0 12 2. 1 1201A 779 1182B 164 186 463 136 588 786 4.0 836 4.0 963 4. 0 470 4.0 148 4. 3 76 4. 5 1062 80 116 826 810 H6* H61* 241 552 676 873 988 1075 800 371 2 4 18 372 383 560 617 651 1091 H13*
f"‘f“.°°.°’.°°.°°.“".‘° oococncnoc-310: I
10 10 10
5 15 20 20 20 10 50 15 15 15 20 10 10 20 20 20 20 20 20 10 10 10 40 20 20 20 20 10 10 15 10 20 10 10 40 15 40 20 15 446 EDGAR H . NORRIS
Table of embryos stud2'ed—C'ontinued
SERIAL NUMBER COLLECTION NUMBER 0. n. LENGTH smcrxox THICKNESS mm. microns 43 221 7. 5 20 44 1354 7.85 20 45 113 8. 0 10 46 1006 8. 0 20 47 389 8.0 20 48 792 8 . 0 20 49 163 9.0 20 50 388 9.0 25 51 721 9.0 15 52 887 9.0 40 53 422 9.0 40 54 452 9.0 40 55 1197 10.0 20 56 114 10 .0 10 57 397 10 . 0 10 58 623 10. 1 20 59 109 10. 5 20 60 1160* 11.0 20 61 H68* 11.0 15 62 353 11.0 10 63 916 11.0 40 64 544 11.5 40 65 1121 11.8 40 66 H134* 12.0 20 67 175 13.0 20 68 695 13. 5 10 69 144 14. 0 40 70 H1* 15.0 12 71 H23* 15.0 10 72 H18* 15. 5 10
3. MORPHOGENESIS OF THE THYROID GLAND
For descriptive purposes the morphogenesis of the thyroid gland is readily divisible into eight stages, as follows:
1. Pre-anlage stage. 5. Complete separation stage. 2. Early anlage stage. 6. Cavity formation stage.
3. Early growth stage. 7. Plate stage.
4. Beginning separation stage. 8. Follicular stage.
This more or less arbitrary division of the developmental process is based entirely upon the changing form and structure of the gland, irrespective of the age and size of the embryo. The relations of these various stages are best set forth in the accompanying diagram (ﬁg. 1).
1. Pre—cmlage stage. This stage may be deﬁned that period in embryonal development between the time of the formation of the entcdermal pharynx and the appearance of the thyroid anlage (ﬁg. 1, a). This stage precedes those represented in the present series.
2. Early cmlage stage. The anlage of the thyroid gland is well formed even in the earliest members of the present series. When first recognizable, the anlage has the form of a fairly deﬁnite and rather extensive though shallow evagination from that portion of the mesobranchial region of the pharyngeal floor which lies between the ventral extremities of the ﬁrst two pairs of gill pouches (ﬁgs. lb, 2, 3). The cavity of the thyroid pouch or diverticulum thus formed is encroached upon and partially obliterated from below by a localized thickening of the epithelium in its ﬂoor. Such a condition occurs in nine of the embryos ranging from 2 to 4 mm. in length (Nos. 1, 2, 3, 4, 5, 6, 7, 8, and 12 of the present series).
3. Early growth stage. VVhereas the gland in the preceding stage is represented by a single typical form, the early growth stage presents three distinct types (ﬁgs. 1,c; 1,d; 1,6). Although these three types are quite different iI1 form, they all result from one process, that of growth. Being derived from a common parent and produced by a like process, the three types apparently owe their differences in form to various distributions of the growth activity in the anlage.
The first type presents the form of a solid pyriform globose bud suspended from the ﬂoor of the pharynx by a short, solid neck (fig. 1, c). There is only a slight depression remaining to indicate the previous existence of a thyroid pouch. This type occurs in Nos. 11, 15, 18, and 26 of the present series.
The second type differs from the ﬁrst in that the suspending stalk is hollow and tube—like rather than solid (ﬁgs. 1,05; 8).
Fig. 1 A schematic interpretation of the process of morphogenesis of the human thyroid gland. With but two exceptions (cl and g), each form included in this arrangement is St seinidiagrammatic drawing of the condition found in sections of embryos. The parts in solid black represent the epithelium of the pharyngeal ﬂoor and the thyroid gland in the various phases of its derivation. For :1 description of the individual units see text. a, pre-anlage stage; I), early MORPHOGENESIS OF HUMAN THYROID GLAND 449
This condition was found in Nos. 13, 14, and 29 of the present series.
The third type is widely dilierent from either of the preceding in that in place of a single bud the gland is already clearly bi,lobed. Two lateral masses, each suspended from the pharyngeal ﬂoor by a short, hollow stalk, joined one with the other by a mound—like fold of epithelium and separated by intervening mesenchyme, represent the thyroid gland (ﬁgs. 1,2; 4). This type of gland was found in but one specimen (No. 17) of the present series.
Fig. 2 Graphic reconstruction of a portion of the foregut of a human embryo 2 mm. long (No. 1) to demonstrate the form and position of the thyroid agilgioge (T.). N., notochord; G’.P.1, first gill pouch; G’.P./9, second gill pouch,
4. Beginning separation stage. This stage, like the last preceding, is represented by three types as regards form. These are apparently later developmental derivatives, one from each of the three preceding types. Each is probably produced by a
3-D1aE_3 Stage} 1’; dy 9; early growth stage, f, a form included to show the probable relationship of e and 2; g, h, 1', beginning separation stage; j,” k, l m n 0 p 41 complete separation stage; 2', cavity formation stage. The ﬁgure Jshdwsi a hrdss: section of a gland having an irregular outline and three closed cavities within (These cavities are entirely different from the follicle cavities, which appeal. 1?-terli 8, plate stage. The ﬁgure shows the cross-sectional appearance of thegland after the primary cavities have begun to open to the outside; t, follicular’ stage.’ The ﬁgure shows a cross-section of an irregular two-celled epithelial’ plate in which follicles are being formed. One follicle has been completely sepa_ ated oli from the plate. 450 EDGAR H. NORRIS
similar process—the lengthening of the suspending neck or stalk. The first type (fig. 1, g), in which the stalk is represented by a solid cord, is hypothetical (not having been found in the series studied), but is included to set forth more clearly the probable
1.. GP. 1 (5:91 3 4 T
Fig. 3 Outline drawing of the epithelial lining of the pharynx of a human embryo 2 mm. long (No. 1) as seen in cross-section. L., lumen of pharynx; Nc., notochord; ’1’., thyroid anlage; G.P.I, first gill pouch. X 100.
Fig. 4 Outline drawing of the epithelial lining of the pharyngeal floor of a human embryo 4.5 mm. long (No. 17) as seen in cross-section. The section is taken through the thyroid gland which appears as a bilobed structure in this specimen. X 100.
Fig. 5 Outline drawing of the epithelial lining of the pharyngeal ﬂoor of a human embryo 6 mm. long (No. 28) as seen in cross-section. The section is taken through the thyroid gland which appears as a biloed b structure suspended from the pharyngeal ﬂoor by a short hollow stalk. (T. D.. thyreoglossal duct) X 100.
Fig. 6 Outline drawing of the epithelial lining of the pharyngeal floor of a human embryo 6.5 mm. long (No. 31) as seen in sagittal section. This section is taken through the thyroid gland which appears as an irregularly bilobed structure suspended from the pharyngeal ﬂoor by a long hollow stalk. X 100.
relations of the earlier and later stages. The second type (ﬁg. 1, h) possesses a long hollow stalk, and is found in embryo No. 35. It differs from the third type (ﬁgs. 1,1’; 6) only in the fact that the body of the latter is bilobed. The third type occurs in embryo No. 28. Between this third type and its predecessor, an extra stage, representing the condition found in No. 31, has been included in the diagram to indicate the way in which the previously bilobed gland probably comes to be suspended by a single hollow stalk (ﬁgs. 1, f ; 5).
5. Complete separation stage. Apparently the thyroid may sever its connection with the pharynx in embryos of various lengths. The earliest instance in which the gland was found free is in an embryo of 3.9 mm. (No. 9). While the oldest specimen Which shows the gland still attached to the pharyngeal floor in this series was found in the case of an embryo measuring 7 mm. in length (No. 35). There also appears to be great variability i11 the form of the gland at the time at which its independence is established. This is well brought out in ﬁgure 1. It will be noted that certain of the glands have been cut off close up to the pharynx, while others have been set free ata much greater distance from the floor of the pharynx by the division of the long suspending stalk. There are four ways in which the stalk may be divided. It may break at the proximal end (pharyngeal) (ﬁgs. 1, j ; 1,m; 1,p), or at the distal end (glandular) (ﬁgs. 1,75; 1,0), or at both (ﬁg. 1, Z); or it may divide midway between the pharynx and the gland-mass so that a portion is left in connection with the pharyngeal floor and the other part attached to'the gland (ﬁgs. 1,71; 1,q).
Before going further with a description of the form of the gland it is desirable to consider in detail the histologic structure of the organ during these earlier stages. As shown in ﬁgure 7, no cell boundaries are found in the earliest members of the series. The cytoplasm has a clear, almost hyaline appearance and only infrequently shows a very few ﬁne scattered granules. The nuclei are fairly typical. They are large ovoidal bodies having very distinct nuclear membranes. In general, the nuclei are so arranged. that their long axes are nearly perpendicular to the surfaces of the anlage. Each nucleus contains three or four large smooth chromatin blocks (karyosomes) which are placed in an almost structureless karyoplasm and lie either in apposition with the nuclear membrane or apparently free in the nuclear sap. A few ﬁne linin ﬁbrils may be made out passing through the karyoplasm and joining two or more of the chromatin masses (ﬁg. 7).
In embryos of 4 mm. (ﬁg. 8) certain other structural differences may be observed. Cell boundaries are beginning to be differentiated and are easily distinguishable in some parts of the anlage. The nuclei instead of being ovoidal or ellipsoidal are much more nearly spherical in outline. The nuclei are also more chromatic, staining more deeply than in the earlier stages.
6. Cavity formation stage. In ﬁgure 1 the early thyroid gland has been somewhat diagrammatically represented as having a
Fig. 7 Small portion of a cross-section of the thyroid gland in a human embryo 2 mm. long (No. 1) highly magniﬁed to show structure. The upper side of the ﬁgure is the side next to the lumen of the pharynx. X 1350.
globular or simple bilobed form and a nearly uniform size. In general this is a correct representation, although there is considerable individual Variation in both respects. This is true not only in the beginning separation stage, but especially after the thyroid has become cut off from the pharynx. Through rapid growth the gland then increases in size and assumes the form of a thick, irregular plate-like mass which is more or less deﬁnitely bilobed (ﬁg. 9). This gland—mass or plate, which averages ﬁve or six cells thick in cross-section, is placed ventral to the trachea in a plane parallel with the long axis of the body.
It should be carefully noted that throughout all the preceding stages (exclusive of the pre-anlage stage and the plate stage MORPHOGENESIS or HUMAN THYROID GLAND 4.53
just mentioned) the gland has existed as a solid, bud—like diverticulum, at ﬁrst suspended from the ﬂoor of the pharynx by a solid or hollow stalk, but later becoming detached and free. In embryos of about 7 mm. there appear Within the gland mass 3. number of completely closed cavities. These intraglandular cavities are at ﬁrst only tiny clefts, appearing very much as though the cells around them had but pulled a little apart. At first the cavities are very small, but they soon increase in
Fig. 8 A cross-section of the pharyngeal floor and the attached thyroid gland in a human embryo 4 mm. long (No. 13), magniﬁed to show structure. X 500.
size and are thus brought more closely into relation one with another. Nothing more can be said by way of generalization regarding their size, shape, or arrangement. Great differences are found in these respects in cavities of the same gland as Well as in glands at different stages of development. In every case the cavity is outlined by a very distinct and sharp margin, and in no case is there any visible content within.
It is important to note that these spaces are apparently quite independent of any external conditions, and in these early stages in no case open to the outside. Furthermore, as shown in ﬁgures 1, 1", 10, and 11, they develop independently of one another as isolated spaces, and only secondarily may become conﬂuent. At a later stage these cavities, for the ﬁrst time, open to the outside and are then invaded by the adjacent vascular mesenchymc (ﬁg. 1, 3). They develop only in those parts of the gland-mass which have attained considerable thickness, and
Fig. 9 Wax reconstruction of the thyroid gland in a human embryo 7.5 mm. long (No. 42). The bilobed condition of the gland is clearly shown. The gland, Whose general surface is smooth, presents thick and thin parts. In the thick portion near the center of the upper border a cavity which has opened to the outside is seen. X 180.
have never been observed in those parts which do not exceed two cells in thickness. Cavities are found in thirty of the specimens studied (Nos. 22, 25, 27, 32, 36, 37, 38, 40, 41, 42, 44, 46, 48, 49, 50, 51, 55, 56, 57, 58, 59, 60, 61, 62, 65, 67, 68, 70, 71, 72).
'7. Plate stage. As a result of the development of these intraglandular cavities, the gland—mass is transformed from a solid MORPHOGENESIS or HUMAN THYROID GLAND 455
body into one which is hollow and whose cavities are surrounded by epithelial plates two cells in thickness. These cavities do not long persist, but, as above mentioned, very soon open to the outside and are invaded by the surrounding vascular mesenchyme. As a result of this process, the gland comes to be made up of a progressively larger number of smooth, two-celled, epithelial plates which anastomose freely with each other and ultimately come to form an extremely complex structure. The gland in this condition, as it is found at the end of the plate stage, is not ﬁgured in the present paper since it has been fully described and ﬁgured in an earlier contribution (Norris, ’16).
Fig. 10 Cross-section of the thyroid gland in a human embryo 7 mnnlong (No. 37), magniﬁed to show structure and the presence of intraglaxidular cavities. X 400.
This process of cavity formation is not the only method by which the epithelial plates are formed. It is, however, the process apparently involved in the initial breaking up of the glandmass, and continues for only a short time. It is superseded by the derivation of plates from those already formed, by processes of budding and growth. Apparently the upper poles of the lateral lobes of the adultgland are formed fromithose secondary plates which grow cephalad. This is believed to be so because, notwithstanding the fact that cavities have never been observed 456 EDGAR H. NORRIS
in this region, there is a progressive increase in the length of the lateral lobes from stage to stage. These plates are regularly two cells thick and are formed independent of any intraglandular cavities. The writer has observed the development of cavities only in those thickened portions of the early gland—mass which in general apparently correspond to the region of the isthmus and lower one-third of the lateral lobes of the adult gland. Many of these points are Well illustrated in ﬁgure 12, which is a model of the thyroid gland and associated structures of an embryo 15.5 mm. long (No. 72). This model not only serves to set forth the structure of the gland while the plates are being formed, but also represents the important stage in which the lateral anlage has just fused with the median.
Fig. 11 Wax reconstruction of the thyroid gland in a human embryo 11 mm. long (No. 60). The upper portion of the model has been removed in order to demonstrate the rclations to the gland mass to the appearances found in crosssection. Three cavities are shown in the thicker portions of the gland. X 150.
8. Follicular stage. The developing thyroid follicles gradually replace the epithelial plates in which they are formed. Figures 1, s, and 1, t, indicate the relation of these two stages. It is unnecessary to describe the process of follicle genesis further than to emphasize the fact that the cavities or lumina of the thyroid follicles are entirely independent of the earlier transient intraglandular cavities described in the present paper, which in turn are independent of the primitive lumen of the thyreoglossal duct. For a description. of the gland structure from the end of the prefollicular period through the remaining period of fetal development the reader is referred to an earlier publication, (Norris, ’16).
4. Discussion and Conclusions
The remarkably early appearance of the thyroid in the human embryo, as has been pointed out by Various observers, is a point of unusual interest. Thus the anlage of the median thyroid is well formed and easily recognizable in the Kroemer-Pfannenstiel
Fig. 12 Wax reconstruction of the thyroid gland and associated structures in a human embryo 15.5 mm. long (No. 7'2). The thyroid gland, which is in the plate stage, simulates rather closely the gross form of the adult organ—t—here being two lateral lobes joined in front of the trachea by an isthmus, which in this specimen is divided into three parts. Ep.Pl., epithelial plate of the thyroid gland; L., larynx; L.T., lateral thyroid; P., parathyroid; Th., thymus; T72, trachea. X 80.
(1.38 mm.) and in the Rob. Meyer embryo No. 335 (1.70 mm.) (Crosser, ’12). Each of these is somewhat younger than the earliest members of the present series and indicate that the thyroid appears much earlier than is shown in the Nonnentafel (Keibel and Elze, ’08) (2.5 mm.). VVhat the meaning of this early development of the gland is cannot as yet be said. It may 458 EDGAR H. NORRIS
be signiﬁcant of the fundamental phylogenetic role of the structure, or of its great physiologic import, or possibly, on the other hand, may only be an expression of the general vertebrate tendency of craniocaudal development. In the latter case, just as the primitive body segments develop in regular succession cephalocaudally, and just as the lateral pharyngeal pouches appear successively in the same direction, so it might be supposed that the thyroid anlage, which lies cephalad to the region from Which the lungs, liver, and pancreas arise, would appear somewhat earlier than these.
Embryo No. 2 of this series is the specimen described by Dandy (’10). Although Dandy states speciﬁcally that no thyroid anlage has made its appearance in this embryo, in describing the foregut he says: “These pouches (referring to the first pair of pharyngeal pouches) are continuous ventrally and unite to form a ventral pouch.” This ‘ventral pouch’ apparently represents the anlage of the median thyroid, as has been noted by Grosser (’12).
The relatively large area of the pharyngeal floor which is involved in the primitive thyroid anlage is a point worthy of notice. This ventral thyroid pouch is very like the first lateral pharyngeal pouch of this same stage, both as regards size and form. As pointed out in the preceding section, this pouch has the form of a fairly deﬁnite and rather extensive, though at first shallow evagination. The ﬂoor of this outpouching becomes thickened at an early stage. Since this condition has been so regularly observed in the early specimens studied in this series (Nos. 1, 2, 3, 4, 5, 6, 7, 8, and 12), and since those isolated cases found in the literature (His, ’85, Broman, ’96, Sudler, ’02, and the Rob. Meyer and Kroemer-Pfannenstiel embryos Grosser, ’12) likewise accord with this description, one is probably justiﬁcd in concluding that this structure is the typical thyroid anlage for the human species.
The apparently discordant descriptions of the early thyroid gland found in the literature are probably not due to inaccurate observations. According to the scheme shown in figure 1, they are explainable rather as normal variations, the successive stages MORPHOGENESIS or HUMAN THYROID GLAND 459
being represented by a progressively larger number of forms. The apparent discord has arisen because only more or less isolated cases have been studied by a single observer. From the investigation of the present large series it has been possible to arrange the various forms found into a system on the basis of which the descriptions afforded by the literature may be harmoniously interpreted. Thus, withbut few exceptions, forms similar to all those included in ﬁgure 1 have been described, more or less adequately, by earlier observers. But no one has undertaken heretofore to correlate these observations, and consequently an appreciation of their relative signiﬁcance has been impossible.
According to thepresent interpretation, the thyroid gland may take one of three courses of development following the anlage stage. In the first type it assumes the form of a solid globose bud connected to the pharynx by a short, solid stalk (fig. 1, c). Apparently such a condition was found in embryos No. 13 and No. 14 of the Normentafel series (Keibel and Elze, ’08), and in the 3-mm. embryo described by Hammar (’O2). In the second type the gland presents an appearance similar to that just described, differing only in that it is suspended by a hollow stalk (ﬁg. 1, d). This is apparently the form of the gland found by Ingalls (’07), Thompson (’07), Kingsbury (’15), and Johnson (’17). The third type, which is clearly bilobed and gives the appearance of a double gland (figs. 1,c; 1,f), is of special interest. Apparently such a structure was also found in embryo No. 16 of the Normentafel series and in the 5-mm. embryo described by Hammar (’02). A peculiar interest attaches to this form from the phylogenetic point of view. The ﬁnding would seem to support the suggestion by Patten (’17) that the median thyroid may be the combined representative of the two glands found connected with the pharynx in certain of the lower forms.
In the beginning separation stage, which is also represented by three types corresponding to those of the preceding stage, the principal changes are found in the stalk by which the gland is suspended. The stalk becomes elongated or drawn out, so that the gland is removed from the pharyngeal ﬂoor for a greater distance than in the earlier stages. The ﬁrst type of this stage (ﬁg. 1, g), which is hypothetical so far as the present series is concerned, apparently corresponds to the condition found by Keibel and Elze (’08) in. embryo No. 21 of the Normentafel series. No previously described cases have been found which correspond to the second type represented by ﬁgure 1, h. There are several cases in the literature in which the thyroid is described as having a form similar in part to both ﬁgures 1, g, and 1, -1'. That is, the gland which is deﬁnitely bilobed is suspended from the pharyngeal ﬂoor by a solid stalk rather than by a tubular connection. Such a condition was apparently found in embryos Nos. 20, 22, 23, and 25 of the Normentafel series, and by His (’85) in embryo S1 (the thyroid of which, however, he described as having the form of a double epithelial vesicle rather than that of a solid bilobed gland), and by His (’91) in embryo Rn.
As indicated in ﬁgure 1 (j, la, l, m, n, o, p, q) the complete separation stage is represented by a variety of forms which differ from one another, as has been already pointed out, as to the form of the gland at the time of its separation from the pharyngeal ﬂoor and upon the ways in which the thyreoglossal duct divides. The variations in this stage serve to explain the developmental processes involved in those cases in which a pyramidal lobe is found (described by His (’91) as developing from the ‘thyreoglossal duct’), as well as those cases in which no such lobe is present (ﬁg. 1, j, k, l, m, 0, p). The development of the so-called ‘lingual rests’ and ‘suprahyoid bodies’ of Streckeisen (’86) are also explainable as arising from conditions similar to those represented by ﬁgure 1, (lo, Z, n, 0, p, q). The variety of forms which the foramen caecum may assume may likewise be accounted for (ﬁgs. 1, j—1, q). Kanthack (’91), "in an article of slight value” (Minot, ’92), has denied that the foramen caecum, the pyramidal lobe of the thyroid, and the thyroid ‘rests’ which have been found in postnatal life, are related to the morphogenesis of the thyroid gland as was ﬁrst pointed out by His (’ 91).
After the gland has established its independence from the pharynx its structure is again altered, as described above, by the development of completely closed cavities within the thicker parts of the gland mass. These cavities, although not previously described in the human thyroid, apparently correspond to the ‘lumen’ which Keibel and Elze (’08) observed in the thyroid of four specimens in the Normentafel series (Nos. 26, 28, 41, 45). They merely mention the presence of these spaces.
Grosser (’l2) states that “the thyroid anlage, before its separation from the pharynx, becomes bilobed with a divided lumen;” but he cites no speciﬁc cases in which this condition was found. Moreover, this generalization receives no support from my studies nor from the researches of other investigators. Since the gland has been regularly found to be solid up to the time of its separation from the pharynx and since the thyreoglossal duct (that part of it Which remains attached to the gland) at this stage of complete separation has in no case iI1 my series presented a lumen, it is evident that these cavities develop quite independently of the original thyroid pouch. Further evidence in favor of this conclusion may be drawn from the fact that a number of these closed cavities or spaces of various sizes have been found in different stages of development not only in many of the glands (Nos. 22, 25, 27, 32, 33, 36, 37, 38, 40, 41, 42, 44, 46, 48, 50, 51, 55, 56, 57, 58, 59, 60, 61, 62, 65, 67, 68, 70, 71, 72), but also in different parts of the gland in the same specimen.
The cavities which I ﬁrst observed in the human thyroid have been subsequently found in the thyroid of Squalus acanthias embryos (Norris, ’17, ’18). In these ﬁsh embryos the cavities appear at a stage in the glandular development which exactly corresponds to the stage of their genesis in the human thyroid. Moreover, the role they play in the two forms is apparently identical. Born (’83), in describing the thyroid glands of pig embryos 7 mm. long, mentions the presence of lumina in the lateral end of the gland mass. He does not include any description of these lumina, but they probably correspond to the cavities described in this paper. Since ﬁnding these intraglandular spaces in the thyroids of human embryos and in those of Squalus acanthias embryos, the author has made a casual study of a number of intermediate forms (pig, sheep, dog, rabbit, pigeon) and has found similar cavities present in the thyroid of each form investigated. It is hoped that these observations may be extended and presented in a subsequent publication. The existence of this same feature of morphogenesis in the thyroid glands of two animal groups so far removed from one another as ﬁsh and man, as well as in the glands of a number of intermediate forms, would probably justify the conclusion that this is a fundamental feature of thyroid development.
Any attempt to interpret these early intraglandular spaces either on the basis of their immediate or general biologic signiﬁcance, although interesting, can be at best only speculative. It might be thought that the immediate purpose and signiﬁcance of these cavities is to be found in the formation of the twocelled plates from which the follicles are later to be derived. On the other hand, if the vertebrate thyroid is the phylogenetic representative of a true externally secreting gland, it might be suggested that these cavities appear in response to a tendency to reproduce the ancient lumen or duct of the ancestral gland. This theory is attractive, inasmuch as it permits of harmonizing the known facts, both anatomic and physiologic, regarding the endocrine function of the thyroid. From this point of view the hypothesis and conclusion of Bensley (’16), “that the thyroid cell represents a true reversal of polarity,” would be quite unnecessary. On the contrary, this phylogenetic theory would offer a plausible explanation of the present structure of the gland and its endocrine function without making it essential to hypothesize a reversal of cellular polarity.
It might be objected that the fact that these intraglandular spaces have no relation to the lumen of the thyreoglossal duct would appear to be a serious obstacle to the theory just advanced. But such a contention is not as formidable as it might seem at first sight, when it is considered that there are no speciﬁc cases described in which the lumen of the thyreoglossal duct is continuous with a cavity in the gland-mass proper. In other words-, since the lumen of the duct does not extend into the body of the gland, any cavities found there must be morphologically independent of it, although they may, as the theory would suggest, be phylogenetically related.
The development of intra—epithelial clefts and spaces is not an unusual occurrence. The lumina of a number of ‘the true glands are formed within solid epithelial sprouts and buds which are the anlages of the future ducts and tubules. The vacuoles in the epithelium of the oesophagus and duodenum which were described by Johnson (’10) and earlier by Keibel and Elze (’08), are also striking examples of this same feature of morphogenesis. In all these instances, however, the spaces ultimately form a connected system of cavities or open into a common lumen. The intra—epithelial cavities of the early thyroid gland, on the other hand, have a very different fate. They open more or less independently of one another to the outside of the gland-mass and are then invaded by the surrounding vascular mesenchyme. Such a process apparently has not been observed in the morphogenesis of any other organ and seems to be quite unique and peculiar to the thyroid gland.
1. The morphogenesis of the human thyroid gland is divisible into the following stages: 1) pre—anlage; 2) early anlage; 3) early growth; 4) beginning separation; 5) complete separation; 6) cavity formation; 7) plate stage; 8) follicular stage.
2. The typical anlage of the human thyroid gland apparently has the form of a fairly deﬁnite and rather extensive, though shallow evagination from the pharyngeal floor between the ventral extremities of the first two pairs of gill pouches. The ﬂoor of this thyroid pouch becomes thickened "at an early stage.
3. Following the anlage stage, the successive stages are represented by a_ progressively larger number of forms. These types differ from one another both as regards "the form of the body of the gland and as regards the condition of the stalk (thyreoglossal duct) by which it is suspended from the pharyngeal ﬂoor.
4. A deﬁnite thyreoglossal duct may or may not be present during the development of a gland.i The duct may be hollow or solid and of variable length. In those cases Where no thyreoglossal duct is formed, the gland is constricted off .close up to the pharyngeal ﬂoor. 464 EDGAR H. NORRIS
5. The time at which the thyroid severs its connection with the pharynx is variable—the period ranging, as regards length of embryo, from 3.9 mm. to 7 mm.
6. In embryos of approximately 7 mm. there appear within the previously solid body of the thyroid a number of completely closed cavities. These intraglandular cavities, which at ﬁrst are small, may increase in size, and sometimes open one into another. Finally they open to the outside, and are then invaded by vascular mesenchyme. A similar process has been observed in the early embryonic thyroid of other forms, including the pig, sheep, dog, pigeon, and dogﬁsh.
7. As a result of the development of these intraglandular cavities, the gland-mass is transformed from a solid body into one which is hollow and whose cavities are surrounded by epithelial plates two cells in thickness. So that when the cavities open to the outside the gland undergoes a corresponding structural modiﬁcation, being changed from a hollow organ to one made up of a complex network of epithelial plates (plate stage).
8. The transient intraglandular cavities are entirely independent of the follicle lumina, which appear later as described in an earlier paper (Norris, ’16).
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