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Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

XVIII. Development of Blood, Vascular System and Spleen: Introduction | Origin of the Angioblast and Development of the Blood | Development of the Heart | The Development of the Vascular System | General | Special Development of the Blood-vessels | Origin of the Blood-vascular System | Blood-vascular System in Series of Human Embryos | Arteries | Veins | Development of the Lymphatic System | Development of the Spleen
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IV. The Development of the Lymphatic System

Sabin FR. The Development of the Lymphatic System in Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

Florence Rena Sabin (1871 - 1953)
Florence Rena Sabin (1871-1953)

By Florence R. Sabin

Recent work on the development of the lymphatics has given us a new conception of the general morphology of the system as a whole. It has related the lymphatics to the vascular system and separated them from the system of tissue spaces. The study of human embryos[1] has sharpened this conception and made it possible to go a step farther, — namely, dividing the development of the system into two stages. The primary stage consists of a series of isolated lymph-sacs, which are clearly derived from the veins, and which become united into a system through two agencies, — (a) by the thoracic duct, which connects these sacs with each other, and (b) by the formation of a secondary opening into the veins at the jugular valves. The secondary stage involves the peripheral growth of lymphatic vessels which sprout from the endothelial lining of these sacs and spread out over the body. The invasion of the body is gradual, and in certain areas never takes place, as, for example, the central nervous system and the skeletal muscles. Since this new conception is not wholly accepted, — in fact, since most of the texts on anatomy and zoology describe the lymphatics as arising out of tissue spaces, — the evidence for the conception presented here will be given in detail as well as certain important general conclusions.[2] The first evidence of the formation of the lymphatic system is the development of symmetrical sacs in the neck, which have been called the jugular sacs. These are found first in a human embryo 10.5 mm. long (S.l.j., Fig. 488) as endothelial-lined sacs just lateral to the internal jugular veins (Sabin, 1909). In the same year Lewis (1909) described the jugular lymph-sacs in four human embryos, finding the beginning of the sac in an embryo 10 mm. long, in which it consisted of a single sac against the vein. In an embryo of 11.5 mm. he found four or five of such small sacs. His four stages are shown in excellent figures. He called attention to the fact (which is, I think, quite clear) that Ingalls (1908), in tracing the origin of the sac in an embryo 4.9 mm. long, was confusing veins and lymphatics. This jugular sac remains as the only sac until the embryo is 20 mm. long. The sac is formed in the following manner. Along the course of the jugular vein in early stages there is a series of branches which form a capillary plexus. Much of this capillary plexus disappears entirely, not being used to form the permanent branches. This destruction of capillaries is one of the fundamental factors in the evolution of the vascular system. In certain places, and first along the jugular vein, at the level of the primitive ulnar and cephalic veins, in embryos between 8 and 10 mm. long, some of the capillary plexus becomes cut off from the parent vein, and remains for a short time as a group of isolated endotlielial-lined spaces close to the vein. The extent of this zone, which probably varies considerably in different specimens, can be seen in Fig. 489, which is from a reconstruction of the jugular sac of the same embryo shown in Fig. 488. These isolated capillaries, the anlage of the lymphatic system, gradually dilate and coalesce to form symmetrica] endothelial-lined sacs, which subsequently rejoin the vein in such a way as to form a valve at the opening (Fig. 492). The time of the formation of the valve is in embryos between 10.5 and 12.5 mm. in length.

Keibel Mall 2 488.jpg

Fig. 488. — Transverse section through the neck of a human embryo 10.5 mm. long, showing the symmetrical jugular lymph-sacs. (Mall's collection, No. 109.) X about 36. A., artery; N.S., nervus sympathicus; N.X., nervus vagus; Oe., oesophagus; P., pericardial cavity; S.l.j., saccus lymphaticus jugularis; T., trachea. The jugular veins are filled with blood and lie just medial to the lymph-sacs.

It is now necessary to prove that these jugular sacs are lymphatics, and. as this involves the use of the injection method on abundant material, it could not be done on human embryos. Conclusive proof that the jugular sacs are a part of the lymphatic system is readily obtained by injecting the lymphatics in the skin of the neck of other mammalian forms, as for example pig embryos, and proving that the lymphatic vessels empty into the sacs. This can be done in pig embryos from 18 to 20 mm. long. Below this stage the sacs could be identified in specimens in which the blood-vessels had been injected. After the position of the sacs had been determined, it was found that direct puncture of the sacs was the best method of obtaining extensive injections of the lymphatics which radiate out from them, thus indicating not only that the sacs are lymphatics but that they are important centres for the radiation of the lymphatic ducts.

That there are two large sacs in the neck of young sheep embryos, and that these sacs are lymphatics, was noted by Saxer (1896). Saxer. however, represents the theory, together with Gulland (1804), that the lymphatics come from tissue spaces, finding that the first lymph-vessels are in the subcutaneous tissue and are present in bovine embryos 25 mm. long. In 1000 Sala described the origin of the posterior lymph-sacs close to the veins in chick embryos. He had, however, no conception of the significance of this discovery; if the earliest lymphatics are sacs close to the veins, the foundation is laid for the theory that the lymphatics grow from the veins to the periphery. Sala says that the posterior sacs arise from the veins and again that they are tissue spaces, two statements which mutually exclude each other. In addition he finds that the thoracic duct arises as solid cords of cells which secondarily become hollowed out into tubes and join the veins. If this be true, it can not, as Von Ebner says in Kolliker's Geweblehre (Bd. 3. p. 682) in regard to these results of Sala's, " Wohl nicht bezweifelt werden, dass die Milchbrustgange beim Hiiehehen selbstandige Bildungen sind und nicbt aus den Blutgefassen hervorsprossen." But it is quite certain that in mammalian embryos the thoracic duct never arises as a solid column of cells. To return to the lymph-saes, their significance as the first lymphatics, together with the fact that the lymphatics grow from centre to the periphery, lays the foundation for the new theory as was brought out by myself in 1901 in the study of the system in pig embryos.

Keibel Mall 2 489.jpg

Fig. 489. — Reconstruction of the right jugular lymphatic sac, shown in solid black against the jugular vein, in a human embryo 10.5 mm. long. (Mall's collection, No. 109.) X about 14. G.N.V., Gasserian ganglion; S.v., sinus venosus; V.c, vena cephalica; Y.c.i., vena cava inferior; V.h., vena hepatica; V.j.i., vena jugularis interna; V.p., vena portse; V.p.c, vena cardinalis posterior;, vena subcardinalis; V.u.(p-), vena ulnaris (primitiva); V.u., vena umbilicalis; TF.6., Wolffian body.

F. T. Lewis then showed, in 1906, that in rabbit embryos the jugular sacs are immediately preceded by a plexus of blood capillaries, so that they themselves are transformed capillaries. During the same year (1908) this method was confirmed in pig embryos by the method of injection by myself and in eat embryos by the method of wax plate reconstruction by Huntington and McClure together. 3 In pig embryos between 10 and 13 mm. long the entire plexus of capillaries external to the jugular vein can be injected from the vein, while in embryos 13 to 14 mm. long the plexus injects less and less from the vein until the sacs are formed. In one specimen the sac itself on one side received some of the ink which had been injected into the vein, showing conclusively that the sacs come from the capillary plexus. In pigs from 15.5 to 16 mm. long the sacs are never injected from the veins, and hence they are either entirely cut off, which condition lasts a short time, or the opening is guarded by a valve. Huntington and McClure (1910) traced this process by a complete series of wax models of the jugular region in cat embryos. The capillary plexus which is the anlage of the sacs, they called " veno-lymphatics." It may therefore be considered as proved that the jugular sacs are lymphatics and that they are transformed veins. The proof that they are the only lymphatics for a considerable time, until the embryo is 20 mm. long, that none of the tissue spaces, coelom, or the arachnoid spaces are a part of the lymphatic system, will be taken up later, in connection with the general consideration of the relation of the lymphatic system to tissue spaces.

The extension of the sac along the jugular vein may be by the addition of more of the capillary plexus, as is suggested by Figs. 490 and 491. These two figures are coronal sections from an embryo 11 mm. long. If they are superimposed, which can readily be done by matching the curve of the arm bud and the cephalic vein, it will be seen that the capillary plexus, the anlage of the lymph-sac, extends from the root of the primitive ulnar vein along the internal jugular vein into the neck. The full series shows that the plexus also extends a short distance into the arm bud along the primitive ulnar vein. The linear extent of the plexus is about 1.2 mm., an increase over the length of the preceding stage, which was 0.7 mm. The plexus is filled with blood, as if the secondary opening had not yet formed, and indeed, though the place of the valve is indicated in Fig. 490 by the projection of the sac into the angle between the internal jugular and cephalic veins, no break in the endothelium could be made out. This fact — that the endothelium shows no break in sections— is the only evidence on which rests the idea that the permanent opening is secondarily acquired. This contrasts sharply with the condition shown in Fig. 492 from an embryo 17 mm long. The valve is first definitely open in an embryo 12.5 mm long, as stated in the table on page 733, at which time the plexus has been transformed into a definite, long, empty sac of the type shown in Fig. 492. The valve is formed by a projection of the lymph-sac deep into the cleft between two veins, and it is so placed as only to be clearly evident in coronal sections. In transverse sections, as can be readily noted by comparison with Fig. 492, the valve is simply a tiny vessel between two larger veins; in sagittal sections it is even more difficult to locate.

'Huntington and McClure in 1907 had advanced the view that the lymphatics came from clefts between the intima of the veins and the connective tissue, calling these clefts "extra-intirnal" anlages; but they retracted this theory, as far as the jugular sacs were concerned, during the following year (1908), and accepted the idea that the jugular sacs are venous in origin, though they think that the rest of the lymphatics are either "extra-intirnal" or of tissue space origin.

Keibel Mall 2 490.jpg

Keibel Mall 2 491.jpg

Fig. 490. — Frontal section through the arm bud of a human embryo 11 mm long, to show the developing lymphatic sacs along the internal jugular vein. (Mall's collection, No. 353.) X about 37. S.l.j., saccus lymphaticus jugularis; V.c, vena cephalica; V.j.i., vena jugularis interna. Fig. 491. — Frontal section through the arm bud of the same embryo as Fig. 489, to show the relation of the lymphatic-sac anlage to the primitive ulnar vein. X about 37. S.l.j., saccus lymphaticus jugularis; V.c, vena cephalica; V.j.i., vena jugularis interna; V.t.l., vena thoracica lateralis; V.u.(p.), vena ulnaris (primitiva).

There is no increase in the length of the sac in embryos between 12.5 and 17 mm. long, but from now on there is a rapid increase in size up to its maximum, which is reached in an embryo 30 mm. long, when the size is 5 mm. in length. This stage, which is an important landmark in several ways, is shown in a series of four figures, — 493, 494, 495, and 501. Fig. 493 is a reconstruction of the primitive lymphatic system in an embryo 30 mm. Jong and shows that the stage which marks the maximum development of the jugular sac shows also all the other sacs and that they have been united into a complete system through the thoracic duct. Theperipheral system is also well under way, even much more than is shown in the figure, for the two stages of the lymphatic system — namely, the primitive central system of sacs and the peripheral system of ducts — overlap in their development. The position of the jugular sac can be seen by comparing Figs. 493 and 494. The level of the section shown in Fig. 494 corresponds with the line on Fig. 493. Both figures show the great size of the sac, it being by far the largest vascular structure in the neck. As shown in Fig. 493 it is now pierced by branches of three of the cervical nerves, namely the third, fourth, and fifth. These nerves help to orient the sac.

Keibel Mall 2 492.jpg

Fig. 492. — Frontal section through the arm bud of a human embryo 17 mm long, to show the open valve of the jugular lymph-sac in relation to the veins. (Mall's collection, No. 296.) X about 26. S.l.j., saccus lymphaticus jugularis; V.c, vena cephalica; V.j.i., vena jugularis interna; Y.u.(p), vena ulnaris (primitiva).

In the embryo 17 mm. long there was a slight extension of the jugular sac into the arm bud. This extension is now much larger, making a definite subclavian sac (S.l.s.) along the primitive ulnar vein (V.u.p.).[3] The jugular sac in this stage shows two other important points, — namely, its relation to peripheral lymphatics, and an extensive bridging of its dorsal border, which is the process by which the sac is transformed into a chain of lymph-nodes. These two processes are closely related in function. In Fig. 493 one enormous superficial lymphatic vessel {V.l.s.), which arises from the lateral surface of the sac, extends out to the skin, and spreads out into a plexus of large capillaries in the subcutaneous layer. One of the smallest of these superficial lymphatics is shown on the left side of Fig. 494.

This group of vessels is the first set of lymphatics to reach the skin. This has been abundantly proved in pig embryos by many injections into the skin (Fig. 507). In pig embryos this set of vessels reaches the skin in the neck at about 18 mm.; in human embryos about 20 mm. long. At this stage no injection of any layers of the skin in any other place except the neck has ever entered lymphatics. The great size of these early lymphatic vessels to the skin is in some sense represented in the adult by the greater size of the vessels of the deep subcutaneous plexus in contrast with the superficial plexus, and calls to mind the size of the subcutaneous lymph-sacs of the amphibia.

Fig. 493. — Profile reconstruction of tie primitive lymphatic system in a human embryo 30 mm. long. (Mall's collection, No. 86.) X about 5.8 C.c, cisterna chyli; L.g., lymphoglandula; N.III., N.IV., and if. V., nervi cervicalis; S.l.jug., saccus lynphaticus jugularis; S.l.mes., saccus lymphaticus retroperitonalis; S.l.p., saccus lymphaticus posterior; £./.s., saccus lymphaticus subclavius; Y.c, vena cephalica; V.e.i., vena cava inferior; Y.f., vena femoralis; V.j.i., vena jugularis interna; Y.l.p., vasa lymphatica profunda; Y.l.s., vasa lymphatica superficialia; Y r., vena renalis; Y.s., vena sciatica; V.u.(p.), vena ulnaris (primitiva I. In Fig. 493 are seen lymphatics extending over the skin of the head as a superficial plexus (V.l.s.) and deep lymphatics (V.l.p.) extending from the subclavian sac along the course of the primitive ulnar vein into the arm bud.

The bridging of the jugular sac along its dorsal border is shown in Fig. 495. The level of this section is also indicated on Fig. 493. This process of bridging or the cutting of the lumen of the sac by bands of connective tissue begins early, being first noted in an embryo 14 mm. long. It is a process by which the sac, originating from a plexus of blood-capillaries, is reconverted into a capillary plexus this time lymphatic in character. This lymphatic plexus is far more extensive than the preliminary bloodcapillary plexus, as may be seen by comparing the early sac of Fig. 489 with the one in Fig. 493, from which the lymphatic plexus is formed, or by comparing the length of the blood-capillary plexus along the vein, 0.3 to 0.7 mm., with the length of the sac, 5 mm.

To complete the account of the jugular sacs as far as they have been studied — that is, up to the stage when the fetus measures 80 mm.— the sac becomes more and more encroached upon by the connective-tissue bridges, until it is transformed into a plexus of lymphatic capillaries, out of which chains of lymph-glands are evolved.

In Fig. 493, beside the jugular-subclavian sac, there are three other sacs, the retroperitoneal, the posterior, and the cisterna chyli. None of these sacs nor any anlage of them has been made out in embryos under 20 mm. in length. The retroperitoneal sac and cisterna chyli are present in a human embryo 23 mm. long, while all three are present in one 24 mm. long.

'18 The retroperitoneal sac was discovered as a part of the lymphatic system by F. T. Lewis (1901-02 and 1906). Baetjer (1908) found in carefully tracing its history in embryonic and fetal pigs, that it is preceded in embryo pigs 17 to IS mm. long by a plexus of capillaries in the root of the mesentery, which drained into the large anastomosing vein at the hilum of the two Wolffian bodies. These capillaries are readily injected from the vein, as is seen in Fig. 496. The same figure shows the large renal anastomosing vein between the Wolffian bodies ventral to the aorta. It also shows well the mass of connective tissue between the vein and the mesentery in which the retroperitoneal sac develops. The plexus retains its connection with the veins until the embryo is 20 mm. long, as is shown in Fig. 497. Other sections of the same series showed more of the ink within the plexus, but this section was chosen to show the connection with the vein. From .this time on, the plexus is readily transformed into a sac, as shown in Fig. 498 in an embryo 23 mm. long, in which the sac is entirely separate from the vein. The sac joins the cisterna chyli, through which it can drain into the thoracic duct and the veins, in embryos 27 mm. long (Fig. 499). These four figures are the best representation that we have of the proof of the transformation of a venous plexus into a lymphatic sac.

Keibel Mall 2 494.jpg

Fig. 494. Frontal section through the jugular lymph-sacs in a human embryo of 30 mm (Mall's collection, No. 86.) X about 9. The level of the section is shown on the reconstruction of Fig. 493. The section shows the complete lymph-sac on the right side and the valve on the left. S.l.j., saccus lymphaticus jugularis; VS., v. innominata; V.j.i., v. jugularis interna; V.l.s., vasa lymphatica superficialis; Oe. , oesophagus; T., trachea.

In human embryos the stage corresponding to Fig. 496, in which there is a plexus of veins ventral to the renal anastomosis, has been identified in an embryo 20 mm. long, while at 23 mm. there is a definite retroperitoneal sac and a cisterna chyli. The retroperitoneal sac lies in the root of the mesentery adjacent to the great masses of the suprarenal bodies and the sympathetic nervous system (S and G.s., Fig 500). It extends from a point opposite the fourth lumbar vertebra anteriorly, to the point where the superior mesenteric artery enters the mesentery. The position of the retroperitoneal sac is also shown in Fig. 493 and its relation to the renal vein in Fig. 501. which corresponds with the line so marked on Fig. 493. The sac has never been found as large in human embryos as it is in the pig. In a fetus 80 mm. long it is represented by a long chain of lymph-glands or a plexus of lymph-vessels which form the anlage of the glands ventral to the aorta. It has recently been shown by Heuer (1909) that injections of the retroperitoneal sac enable one to follow the progression of vessels from this sac out into the mesentery along the superior mesenteric artery. Within the mesentery is formed a secondary great lymphatic plexus, the anlage of the lymphoglandulas mesentericae (Lg.m.), as shown in Fig. 502. From the mesenteric vessels lymphatics gradually invade the intestinal wall.

File:Keibel Mall 2 495.jpg

Fig. 495. Frontal section through the jugular lymph-sac of the same embryo, at the level shown In Fig. 493, to show the bridging of the sac which is the anlage of the first lymph-gland. X about 19. S.l.j., saccus lymphaticus jugularis.

File:Keibel Mall 2 496.jpg

Fig. 496. Transverse section through the renal anastomosis of the subcardinal veins of an embryo pig 18 mm long. (After Baetjer.) X about 43. A., aorta; G.A., genital anlage; M.C., retroperitoneal capillaries; Mes., mesentery; R.A., renal anastomosis; W.B., Wolffian body.

The posterior lymph-sac has as yet been identified only in pig and in human embryos among mammals. It has, however, been worked out in chick embryos by Sala (1900), where it is a true lymph-heart with muscle in its wall, as in the amphibia. Sala's work has already been referred to; it is the most recent work based on the theory, also brought out by Gulland (1S94) and Saxer (1896), that the lymphatics arise from tissue spaces, unless one includes the work of Huntington and McClure who hold a modified form of this theory (1910). Sala found that the posterior lymph-hearts begin at the middle of the seventh day in connection with the lateral branches of the first five coccygeal veins. He says that corresponding to these veins there are excavations in the mesenchyme which soon enter into communication with the lateral branches ("E sono rappresentati da spazi scavati nel mesenchima che sta laterahnenti ai miotomi caudali, a livello delle prime cinque vene coccygee," p. 292) ; and in fact one would say that these fissures are simply dilatations of the veins themselves (" Si direbbe anzi che esse non sono che semplici dilatazioni, ramificazioni delle stesse vene," p. 269). These two statements, of course, contradict each other, for spaces can not be both fissures in the mesenchyme and dilatations of the veins. Then he describes these fissures as becoming more abundant and confluent. By opening up communications with each other they form a sac or lymph-heart in the mesenchyme. This sac, he says, is lined with flattened mesenchyme cells, which, if it were so, would, according to our stand-point, exclude it from being a vein. He found muscle in the wall of the hearts on the ninth day, and was able to inject the heart directly by the second half of the tenth day. Sala's description of the origin of the posterior lymph-hearts in the chick is, nevertheless, so clear and graphic, and corresponds so closely with the method of origin of the lymphsacs in mammals, that one easily suspects that the two processes are the same, — that the sacs arise from the veins in both cases. The fact that Sala uses the description as evidence of the old conception, of the lymphatic system as coming from tissue spaces, does not necessarily confuse the picture. Mierzejewski (1909), working on the chick, has confirmed Sala's description, and evidently is of the opinion that both Sala and he find the sac arising from the veins, for he states that "An den Enden der lateralen Aeste der ersten fiinf Coccygealvenen bilden sieh kleine, blasenartige Ausbuchtungen, die sich bestandig vergrossern und am siebenten Bebriitungstage eine Reihe von segmental nacheinanderfolgenden, mit den Vene in Verbindung stehenden Spalten im embryonalen Bindegewebe bilden. Diese Anlagen des spateren Lymphherzens nehmen im Verlauf der Entwicklung an Grosse zu und nahern sich einander immer mehr und mehr, so das sie schlieszlich miteinander an den Stellen, wo sie beriihren verschmelzen." He also states that he agrees with Sala, except that the process begins a little earlier than Sala described, — namely, in the middle of the 6th rather than the beginning of the 7th day. Thus it seems a fair conclusion that the weight of evidence from the study of the posterior hearts in the chick is on the side of their venous origin.

File:Keibel Mall 2 497.jpg

Fig. 497. Transverse section through the renal anastomosis of the subcardinal veins in an embryo pig, 20 mm. long. (After Baetjer.) X about 43. In this section the venous channels in the root of the mesentery are beginning to show definite evidences of fusion and sac formation, though they are still connected with the veins, as is shown in the figure. A., aorta; G.A., genital anlage; M.C., retroperitoneal capillaries; Mes., mesentery; R.A., renal anastomosis; W.B., Wolffian body.

  • In a human embryo 20 mm. long there is a plexus of capillaries along the v. ischiadica which forms the anlage of the posterior sac.

File:Keibel Mall 2 498.jpg

Fig. 498. — Transverse section through the rena anastomoses in an embryo pig 23 mm long. (After Baetjer.) X about 53. This is the first appearance of a definite sac in the exact location of the venous plexus in the earlier stages. It will be noticed that the irregular margins suggest the fusion of many small vessels. At this stage no connection can be traced between the sac and either the lymphatic system or the veins. A., aorta; M.S., retroperitoneal sac; R.A., renal anastomosis; W.B., Wolffian body.

The saccus posterior or ischiadicus is first found in an embryo 24 mm. long, and is well shown in Fig. 493 in the embryo 30 mm. long. Here it is a long narrow sac — seen also on one side in Fig. 501 — which extends along the external surface of the v. ischiadica primitiva (S.l.p.), from the posterior end of the cisterna chyli to the bifurcation of the v. femoralis and the v. ischiadica. The sac reaches an apparent maximum in fetuses 80 mm. long. It is shown to great advantage in sagittal section in a fetus 80 mm. long in Fig. 504. The posterior sac is now clearly a pelvic structure, being transformed into a chain of lymphoglandulae iliacae.

The question of the origin of the cisterna chyli and the thoracic duct has proved a difficult problem because the region is hard to eject.

Recent studies on pig embryos throw some light on the thoracic duct. In a pig embryo 23 mm. long (measured fresh along the mesencephalosacral line; compare Chap. VIII) the left jugular sac was filled with ink through the superficial lymphatics. The needle was then withdrawn and pressure applied to the head. By a fortunate chance most of the ink ran over into the thoracic duct while very little ran into the veins. Usually the ink passes readily through

File:Keibel Mall 2 499.jpg

Fig. 499. — Transverse section through the early cisterna chyli and retroperitoneal sac in an embryo pig 3 cm. long. (After Baetjer.) X about 40. The section shows the connection of the cisterna chyli and the retroperitoneal sac, by large channels along the lateral margins of the aorta. A., aorta; K., kidney; I., intestine; M.S., retroperitoneal sac; R.C., cisterna chyli; P.C.V., postcardinal vein.

the valve into veins. In this specimen it can be shown that the jugular sac anlage of the thoracic duct has three connections with the jugular sac, and passes as a plexus of lymphatic vessels toward the median line between the sympathetic nerve and the common jugular vein (these relations can be made out in Fig. 48S). The two ducts, the thoracic duct and the right lymphatic duct, extend in the loose connective tissue dorsal to the oesophagus about to the level of the arch of the aorta. At this stage there are no lymphatics corresponding to the eisterma chyli, but there are especially abundant median anastomoses of the posterior cardinal or azygos and hemiazygos veins dorsal to the aorta opposite the adrenal anlages.

In the next stage — namely, in an embryo 25 mm. long — the jugular sac anlages are more extensive and now symmetrical, for the right duct has turned ventralward toward the root of the lung while the left, or thoracic duct, remains near the aorta. A second change of importance has taken place, — namely, the separation of a new lymph-sac from the veins, the cisterna chyli, which exactly replaces the previous plexus of veins. An abundant plexus of lymphatic vessels encircles the aorta from this cisterna chyli, so that one can not in this region speak of a right and left duct, but rather of an aortic plexus. This fact is interesting in comparison with Pensa's (1908 to 1909) figures showing the comparative morphology of the duct in various forms, for he shows that in a number of forms the lower part of the thoracic duet is an abundant plexus of lymphatic vessels. By the time the pig is 27 mm. long the relations of the three prevertebral lymphatic anlages are established, the right lymphatic jugular sac anlage, making the right duct, has reached the root of the lung, while the left jugular sac anlage has anastomosed with the cisterna chyli anlage along the aorta, making the thoracic duct. All the specimens studied show some isolated endothelial-lined spaces which cannot be traced to connect with the thoracic duct in serial sections. The existence of these isolated spaces was pointed out by Lewis (1906), and, since he could trace a few of them to join veins, he suggested that there might be multiple venous anlages of the lymphatic vessels analogous to the lymph-sacs. Since these spaces or isolated islands are found along other veins as well as the azygos veins, they will be discussed under the general considerations (p. 737). The other recent work on the thoracic duct is by McClure (1908), in which he agrees with Lewis that the thoracic duct arises by multiple anlages from the veins. This view he retracted in 1910 in favor of the extra-inthnal theory; but, since he did not retract the evidence in his first paper but only the interpretation of the observations, it must be stated that he confused veins and lymphatics, calling certain veins lymphatic anlages, when it is easy to demonstrate that these same veins persist as veins after the thoracic duct is formed.

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Fig. 500. — A composite diagram made by superimposing the sections showing the relations of the retroperitoneal sac and cisterna chyli to the veins, in a human embryo measuring 27 mm. (Mall's collection, No. 382.) X about 8. A.m.s., a. mesenterica superior; C.c, cisterna chyli; G.s., ganglia sympathies; S.l.m., saccus lymphaticus retroperitonealis; S., suprarenal body; Y.a., v. azygos; v. c.i., vena cavainferior.

In human embryos the observations on the thoracic duct are still scanty. In the embryo shown in Fig. 488, which is 10.5 mm. long, there is on the left side a small vessel extending from the sac toward the median line. In an embryo 16 mm. long there are symmetrical jugular sac anlages of the thoracic and right lymphatic ducts, which, however, do not reach the zone dorsal to the oesophagus. The first appearance of the cisterna chyli is in an embryo 23 mm. long, as shown in Fig. 500. Here it is a definite sac opposite the third and fourth lumbar vertebrae, at the point where the vena cava curves ventralward and where it anastomoses with the azygos vein. By the time the embryo is 30 mm. long, as shown in Fig. 493, the thoracic dnct is complete. The lower or cisterna chyli portion is much simpler than in the pig embryos, in fact there is a right and a left vessel, and the right duct crosses behind the aorta in the thorax to join the left. Thus the human embryos illustrate the double origin of the duct from the jugular sacs on the one hand and from the cisterna chyli, a true lymph-sac, on the other.

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Fig. 501. — Frontal section through the retroperitoneal sac of the human embryo, at the level indicated on Fig. 493. X about 40. A., aorta; G.s., ganglia sympathica; K., kidney; S.l.m., saccus lymphaticus retroperitonealis; S.l.p., saccus lymphaticus posterior; V.c.i., vena cava inferior; V.r., vena renalis.

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Fig. 502. — Transverse section through the abdominal cavity of a human embryo 80 mm. long. (Mall's collection, No. 172.) X about 8. A.m. a., arteria mesenterica superior; C.c, cisterna chyli at its lower border; Lg.m., lymphoglandulse mesenteries ; S.l.m., saccus lymphaticus retroperitonealis.

The question of the peripheral growth of lymphatics is one which really lies at the root of the new conception of the origin of the lymphatic system from the veins. In studying the peripheral lymphatics it was found that they converged toward or radiated out from certain centres. These centres proved to be the lymphatic sacs. The lymphatic sacs become united into a system by means of the thoracic duct, and connected with the veins by the development of valved openings. The sacs and thoracic duct may be termed a primary system, which is shown on Fig. 493. The secondary or peripheral lymphatics, according to our view, grow out from the primary system. In tracing the peripheral lymphatics we may refer again to Fig. 493, which shows not only the primary system of sacs complete but the beginning of the peripheral vessels. The earliest peripheral lymphatics that have been made out in a human embryo are those from the jugular sac to the skin of the neck in an embryo 20 mm. long. These vessels are shown (V.l.s.) in the embryo 30 mm. long in Fig. 493, and again as the large deep vessel behind the ear and pointing toward the shoulder in Fig. 505. At the stage of 30 mm., beside the superficial vessels for the back of the head, there are deep lymphatic vessels (V.l.p.) extending along the subclavian vein. The transformation of the jugular subclavian sac into a chain of lymph-glands makes the primary group of glands for these two sets of vessels. In Fig. 493 is shown a small gland (Lg.) on the course of the plexus of lymph-ducts at the edge of the subclavian sac. This marks the beginning of secondary glands, that is those that form on the course of lymph-ducts. From the posterior sac two sets of peripheral vessels are extending, one along the v. femoralis, shown as V.l.s., while the second set, which follows the V. ischiadica to the hip, is not shown. The vessels along the v. ischiadica have, however, reached the skin and spread out over hip and back at this stage, as can be seen for the pig in Fig. 507.

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Fig. 503. — Sagittal section of a human embryo measuring 50 mm., showing the posterior lymph-sao within the pelvis and its extension along the femoral vein. (Mall's collection, No. 96.) X about 8. F., femur; La-, lymphoglandula (femoralis); O.s., os sacrum; S.l.p., saccus lymphaticus posterior with lymphgland in the border; V.s., vena sciatica; V.I.V., vetrebra lumbalis V.

Recently I have had the privilege of studying a remarkable specimen of a lymphatic distention in a human embryo. The embryo, which is 5.5 cm. long, was injected through the umbilical artery bv Professor Max Broedel while the heart was still beating. It was then placed in formalin and left there for about a year. Dr. H. M. Evans then began to study the vascular injection in the skin vessels, and while working on it put the embryo into freshly made-up 50 per cent, alcohol. To his amazement, there appeared a wonderful injection of air in the skin, which proved to be a complete injection of the superficial lymphatic system. The irregular lymphatic plexus shown in silvery lines was of great beauty. Two tracings were made of the specimen under direct sunlight, with the aid of a camera lucida, one a side view shown in Fig. 505, the other a dorsal view, Fig. 506. The injection gradually disappeared, but for a few days could be restored by the use of fresh alcohol.

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Fig. 504. — Transverse section through the pelvis of a human embryo 80 mm. long, to show the posterior lymph-sacs. (Mall's collection, No. 172.) X about 9. S., bladder; Lg., lymphoglandula; if., rectum;, saccus lymphaticus posterior.

The specimen is of the same stage as the largest pig embryo figured in my article (1904) on the superficial lymphatics, and the two specimens make an interesting comparison. It is the stage of the single primary lymphatic plexus, and only in one area, namely in front of the ear, was there a double plexus, deep and superficial.

Notwithstanding the great irregularity of the plexus, a quite definite pattern is to be made out. The vessels all drain into two areas, as shown on the side view. First the vessels from the head, neck, arm, and thorax run toward the jugular-subclavian sac, and secondly those from the leg, hip, and abdominal wall run toward the groin to the posterior sac. These points of drainage are marked on the surface by the few large definite trunks that radiate toward them. The vessels which drain toward the neck and axilla — namely, the trunk behind the ear and the pectoral trunks below the arm — have valves. The vessels on the abdominal wall pointing toward the groin are large and irregular, but are as yet without definite valves. Valves are wanting in all the rest of the vessels. It is striking how completely the entire lymphatic plexus anastomoses, so that theoretically one can inject the entire lymphatic system through any one vessel whatever. The natural flow of lymph toward the sacs, however, is indicated by the size of the main trunks.

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Fig. 505. — Distention of the lymphatic vessels with air of a human fetus 5.5 cm. long, drawn by means of a camera lucida. (Mall's collection, No. 448.) X about 2. The drawing had to be completed without the object, a-b, area without lymphatics.

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Fig. 506. — Distention of the lymphatic vessels with air in the same fetus as in Fig. 505.

The extent of the injection is most interesting. There is a small area on the head in the mid-line (between the letters a and b in Fig. 505) which never showed any lymphatics. It is the same area, only less extensive, that could never be injected in the pigs of this stage, and thus is probably entirely free from lymphatics. The fingers, toes, the palms of the hands, and soles of the feet likewise had no injection whatever.

The pattern of the vessels over the head shows a number of interesting points. Over the face the mesh is much finer than over the scalp. The eyelids show a few vessels, the ear none. Behind the ear is shown a large deep trunk, seen in both figures, which drains the back of the head and neck and undoubtedly enters the jugular sac or gland. This trunk is to be compared with the vessel marked V.l.s. in Fig. 493 and in Fig. 494. There is probably also a deep, large channel in front of the ear, for the vessels of the face and chin converge there, but the double plexus of capillaries was so dense there that none could be made out. On the back of the head, long parallel vessels drain toward the jugular trunk on either side, while in the centre the plexus is fine-meshed toward the top of the head and coarse-meshed toward the neck. The vertebra prominens is marked by being rather free from lymphatics, and the same is true of the bony prominences at the elbow and ankle.

The arm shows a fine-meshed plexus; the vessels reach the cleft between the fingers in each case. The pattern of the forearm is made by long parallel vessels running lengthwise, while in the upper arm the vessels run around toward the axilla.

The plexus over the ventral surface of the body is fine-meshed, and there is a complete anastomosis across the mid-line ; over the back the plexus is coarse-meshed. A few large vessels over the chest and back drain toward the axilla; a similar set converge to the groin. The latter do not yet show valves. The especial characteristic of the back region is that the mid-line is bridged by long, rather slender parallel vessels. This is more marked in the lower third.

On the foot the vessels reach the clefts between the toes just as on the hand they reach the clefts between the fingers. The malleoli are quite free from vessels. On the leg the vessels run obliquely rather than lengthwise on the lateral aspect, while on the thigh the plexus points toward the groin.

The double injection of blood-vessels with Prussian blue and of the lymphatic capillaries with air enabled one to see their relative positions with great clearness. The large main blood-vessels of the skin were deeper than the lymphatics, while the entire system of smaller arteries and the blood-vascular capillary plexus lay superficial to the much larger lymphatic plexus.

The development of the peripheral lymphatics out from the sacs to the ultimate capillaries has been worked out in the skin of the pig, of the bird, (Mierzejewski, 1909), and of bovine embryos (Polinski, 1910). In the skin (Sabin, 1904) a great number of injections have brought out the fact that the vessels spread out from two great centres, the neck and the groin, so that the vessels gradually extend from lymphatic to non-lymphatic areas. Fig. 507 will serve to show the spreading out of the lymphatics in the primary subcutaneous plexus. The group in the neck is growing out from the jugular sac, the group over the hind leg is extending from the posterior sac. Both of these injections are complete or nearly so, showing that there is a large non-lymphatic area at this stage. Later a secondary, finer-meshed, and more superficial -plexus develops. From the retroperitoneal sac, the peripheral spread of the lymphatics to the ultimate lacteals of the intestine has been worked out by Heuer (1909) in the pig. Fig. 50S, taken from this paper, shows the entrance of the groups of lymphatics from the mesentery into the intestinal wall, and the primary submucosal plexus not yet complete. Later a finer-meshed plexus forms in the mucosa, and from this plexus the lacteals grow into the villi.

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Fig. 507. — The lymphatic vessels of the skin of an embryo pig 4.3 cm. long. X about 2H- The injected vessels form the primary subcutaneous plexus and represent a complete injection except in the area dorsal to the ear, — that is to say, the uninjected areas have not yet received lymphatics.

This point of the gradual progression of the lymphatics within an organ out to the ultimate eapilliaries, which is one of the strongest proofs of the growth of lymphatics from the veins to the periphery, rather than from the periphery to the veins, is also very convincingly shown by H. M\ Evans. Fig. 509 is taken from this paper, which describes a case of sarcoma of the intestine in which there is a growth of new lymphatics out into the tumor mass. It will be noticed that the growth is from the mucosal or capillary plexus, that at the edge of the tumor the new vessels are like normal lacteals, while within the nodule there is an over-development of lymphatics in the form of an advancing plexus. It has also been pointed out to me by Dr. Evans that in the adult intestine the valves of the lymphatics occur at the base of the capillary bed, that is in the submucosal duets, and that they mark the place of transition between the duct and the capillary. Thus the mucosal plexus and the lacteals are the ultimate capillaries. This agrees with the general theory of Ranvier, that in the lymphatic system vessels without valves have the structure of capillaries. The discovery that the lymphatic vessels invade each organ, that the invasion can be demonstrated by injections of successive stages as soon as the line of growth or point of entrance is known, together with the fact that the valves develop at the base of the capillary bed, gives us the key by which the relations of the lymphatic system within each organ can be worked out from the primary distributing plexus of ducts to the ultimate capillaries. It may be well to note here that the lymphatics as they enter an organ are always capillaries, that is the growing zone is always the capillary bed.

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Fig. 508. — Loop of the small intestine of an embryo pig 100 mm. long, to show the growth of the lymphatics into the intestine, and the formation of a primary submucosal plexus out of a series of lymphatic loops. (After Heuer.)

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Fig. 509. — A piece of adult intestine showing a sarcomatous nodule which is being invaded by growing lymphatic capillaries from the mucosal, plexus. The transition from the normal lacteal; to the new vessels is to be noted in passing from right to left. The large submucosal ducts are seen in the shaded area. (After Evans.)

To sum up, the peripheral spread of lymphatics thus far observed in human embryos, from the jugular-subclavian sac, two sets of vessels extend, one to the skin of the head, neck, and shoulder, the other as deep lymphatics to the arm. From the posterior sac two sets of vessels develop, one along the v. ischiadica to the skin of the hip and back, a second set along the v. femoralis to the leg (Fig. 493). The retroperitoneal sac sends vessels into the mesentery (shown as Lg.m. in Fig. 502). On the course of these vessels a mass of lymph-glands develops and vessels extend out from these glands to the intestine. The cisterna chyli drains both the retroperitoneal and the posterior sacs (Fig. 493). The progression of the lymphatics in the Mall collection is summed up in the following table.

In regard to the development of lymph-glands the series of human embryos serves to establish an interesting general relation and to illustrate certain phases in the development of an individual gland. In general, the first stage in the development of an embryonic lymph-gland is the formation of a plexus of lymph-ducts. This was one of the earliest points established and goes back to the time of Breschet (1836). The first lymphgland to appear is through the transformation of the jugular lymph-sac into a plexus of lymph-vessels. This bridging of the sac is shown in Fig. 495, and is simply a reduction of the sac into a plexus of lymph-vessels lined with endothelium, with bridges of connective tissue between, in which the mesenchyme is slightly denser than in the surrounding tissue. All the primary lymphsacs are thus transformed into a plexus of lymph-vessels. In the jugular sac the transformation extends over a series of embryos and fetuses from 14 to 80 mm. long. The bridging of the retroperitoneal sac is illustrated in Figs. 501 and 502, in the posterior sac in Figs. 503 and 504. The cisterna chyli becomes bridged only along its borders[4] (Fig. 502). Primary groups of glands may be defined as those which develop from the lymph- sacs. They are the jugular-subcl avian chain, the retroperitoneal or pre-aortic chain, and the chain of lymphoglandnlse iliaea?. All the lymph drains through these chains.[5] Secondary lymph-glands develop around plexuses of the peripheral vessels, and two of these are shown in Fig. 493, one in the arm, and the second in the leg. The secondary group from the retroperitoneal sac is shown in Fig. 502 as the mesenteric group of glands (Lg.m.). The ultimate lymph-glands which develop at the base of the final capillary bed as the lymphfollicles of the intestine were not found in the series ; they are probably the last to develop. This is in harmony with the findings of Anton (1901) in connection with the lymph-glands of the Eustachian tube and the middle ear. He found no glands there in the fetus, while during the first two years of life there was a gradual development of lymphocytes which subsequently formed definite follicles.

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Fig. 510. — Reconstruction of an axillary ymph-node anlage from a human embryo 70 mm. crovn-rump, showing the primary plexus of lymphatic capillaries. (After Kling.) X about 41.6. 6, the bands of connective tissue between the lymphatics; these are shown as darker than the lymphatics; d, dorsal; I, lymphatic vessels; Is, blind end of a sprouting lymphatic capillary.

In regard to the development of an individual node, the important stages can be well illustrated in human embryos.[6] The first step in the formation of lymph-glands is a plexus of lymphatic capillaries, and this is true whether the gland forms out of one of the primary sacs or along the course of peripheral lymphatic vessels. This first stage of a lymph-gland is illustrated in section in Fig. 495 for the jugular lymph-gland in an embryo measuring 30 mm. long. The character of the lymphatic plexus is also well shown in Fig. 510, after Kling, from a reconstruction of the subclavian or axillary group of a fetus somewhat larger, measuring 70 mm. In the primary stage the lymph-node is wholly lymphatic in structure, — i.e., it consists of a plexus of lymphatic capillaries with undifferentiated connective-tissue septa.

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Fig. 511. — Reconstruction of a lymph-node from a human embryo 270 mm. long, showing the peripheral and central sinuses. (After Kling.) X about 41.6. b, connective-tissue bands; sin.m., sinus marginalia;, intermediar sinus; vas.a., vas afferens; vas.e., vas efferens.

The second step of the development of the node is the heaping up of lymphocytes or wandering cells in the connective-tissue septa, forming follicles. These masses of cells are shown in Kling 's first model as the darker masses labelled b, some of which are oval, while more are irregular in shape. In our series the first definite follicles are found in a fetus 50 mm. long. The follicles are associated with a plexus of blood-capillaries. All the recent investigators note these blood-capillaries in the connective-tissue septa. Thus, in the second stage a lymph-gland contains two elements, a lymphatic element, or the plexus of lymphatic capillaries, and a vascular element, consisting of blood-capillaries surrounded by lymphocytes in the meshes of the connective tissue, making the follicles. The follicles are well shown in Figs. 503 and 504. The first two stages, while they can be sharply separated in a series of early embryos, in later embryos develop side by side.

The third stage in the development of a gland is the formation of the sinus out of the plexus of lymphatic capillaries. That the sinus is a capillary plexus, as dense as the blood-vessels in cavernous tissue, is shown most beautifully for the adult in the injections of lymph-glands in Teichmann's Atlas. The reorganization of the node, the development of the peripheral and central sinuses, together with the great increase in the follicle, is well shown in Fig. 511, after Kling. It shows a model of the lymphatic part of a lymph-gland from a fetus 270 mm. long. The very great size of some of the vessels of the marginal sinus is to be noted. In the development of the various nodes the greatest possible variations occur in the proportion of the lymphatic element or follicle. The sinus formation is also shown in Fig. 504. The sinus differs from the primary lymphatic plexus in the extreme thinness of the connective-tissue septa. It remains to be shown whether it differs also in the nature of its endothelium, — that is, whether the sinus, which begins as a dense plexus of closed lymphatic capillaries in fetal stages, is a closed system in the adult or not.

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Fig. 512. — Hemal node from the neck of an embryo pig 245 mm. long. B.v., blood-vessel at hilum; C.b.c, central blood-capillary; P.b.s., peripheral blood-sinus.

In the alimentary canal there are certain special lymph-glands — namely the tonsils, solitary follicles, and Peyer's patches — that develop in the capillary bed close under the epithelium. In connection with these nodes there has been considerable confusion in regard to their development. This confusion was the more easy as long as it was thought that the thymus, derived as it is from epithelium, was lymphoid in character. Stohr (1S91 and 1898) and Kollmann (1900) have pointed out that the lymph-nodes in the mucosa of the alimentary canal are mesodermal in origin, as is all the rest of the lymphatic system, rather than ectodermal.

Hemal glands have not been found in human embryos. In pig embryos they appear only in late stages, the first and simplest type, shown in Fig. 512, being found in the neck of a pig 245 mm. long. Here the gland consists of a single follicle around a plexus of blood-capillaries and surrounded by a sinus of bloodvessels. It is thus possible to define the follicle as a collection of lymphocytes around a blood-capillary plexus. The follicle is surrounded by a sinus which may be made of a plexus of lymphatic capillaries forming a lymph-sinus, or by a plexus of blood-capillaries making a blood sinus. The lymphatic sinus is found in the lymph-glands, the blood-sinus is found in the hemal node and in the spleen. A group of lymph-follicles makes a lymph-gland; a group of blood follicles makes a hemal node. In shape the follicle is primarily round, but where the lymphocytes extend along the course of the artery the follicle becomes elongated into the ellipsoids of the spleen or the cords of the lymph and hemal glands. Meyer (1908) showed, by hundreds of injections of haemolymph or better hemal nodes, that they are not connected with the lymphatic system nor are they intercallated in the course of the veins.

General Considerations

It is now necessary to bring out certain general considerations which follow from the recent studies on the lymphatic system.

The relation of the lymphatic system to tissue spaces has been one of the greatest questions in connection with the system since it was first vaguely suggested by Aselli (1622) about three centuries ago, and clearly formulated by Lieberkiihn (1760) in connection with the discovery of the central lacteals of the villi and the supposed opening of these lacteals into the connective tissue. The histoiy and bearing of this great question were best brought out by His (1863). The general conception of the morphology of the lymphatic system has passed through a series of phases. The early experiments of Nuek (1691), of injecting air into the arteries and noting its return through the lymphatics, led to the theory of the connection of the finest arteries and lymphatics. These hypothetical connections may be grouped together under one general term by which they were known, namely vasa serosa.

The vasa serosa are associated with a variety of names, notably Boerhaave, Haller, and Bichat (1818). It was the theory of Haller that the vasa serosa were so small that the red blood-corpuscles could not pass through them, and hence only the fluid of the blood ran over into the lymphatics. As the methods of injecting the fluids were perfected it was noted that only in exceptional cases did fluid forced into the arteries enter the lymphatics. But these observations did not have as much weight in overthrowing the theory of vasa serosa as the development of the ideas of Schwann (1S39) and especially of Virchow (1863). From Schwann's observations on the capillaries in the tadpole's tail, he suggested, in connection with his discovery of cells in the animal body, that capillaries were a network of anastomosing cells making canals all over the body.

Virchow overthrew the idea of the vasa serosa, as will be seen in the following quotation from the English translation of his Cellular Pathology (p. 76): "Amongst these different species of connective tissue, the most important for our present pathological views are, generally speaking, those in which a reticular arrangement of cells exists, or, in other words, in which they anastomose with one another. Wherever, namely, such anastomoses take place, wherever one cell is connected with another, it may with some degree of certainty be demonstrated that these anastomoses constitute a peculiar system of tubes or canals which must be classed with the great canalicular system of the body, and which particularly, forming as they do a supplement to the blood and lymphatic vessels, must be regarded as a new acquisition to our knowledge, and as in some sort filling up a vacancy left by the old vasa serosa, which do not exist." Thus Virchow substituted the idea of hollow connective-tissue cells to connect arteries and lymphatics for the vasa serosa. The methods of injection, however, led to sharper and sharper conceptions of the lymphatic capillary, and made, as His (1S63) says, the obscure lymphatic roots more and more of a myth. The beautiful injections of Teiehmann, together with his own work, led His (1861) to formulate the opinion that "Die ersten wurzeln des Systems durehweg der eigenen, isolierbaren Wand entbehren, es sind Kanale in das Bindegewebe der Cutis, der Schleimhaute usw. eingraben. (Online Editor - The first roots of the system, on the other hand, are without their own, isolable wall, and channels are buried in the connective tissue of the cutis, the mucous membranes, and so on.)"

The next great step was the discovery that capillaries are lined with endothelium, one of the most important discoveries in histology. This dates back to the work of Hoyer in 1865. The names of Kolliker, Teiehmann, His, Hoyer, Ludwig, and von Recklinghausen are to be associated with the development of the conception of a lymphatic capillary as an endothelial lined structure, either in the form of a network or as blind ends like the lacteals. The introduction of silver nitrate injections by Hoyer (1865), His (1863), and von Recklinghausen gave a method by which the limits of the endothelium of the lymphatics were more sharply determined; but the silver-nitrate pictures led von Recklinghausen astray, as we believe, to a conception of lymph radicles or tissue spaces as a part of the lymphatic system. The stomata and stigmata by which the lymphatic vessels were thought to connect with the lymph radicles have not been confirmed, and are more and more clearly seen to be mechanical defects of the silver-nitrate method. The question now presents itself in two phases, first the relation of the lymphatics to the tissue spaces in general, and secondly to certain special tissue spaces like the piarachnoid.

To the first important question, the theory that the lymphatics come from the veins has a perfectly clear and satisfactory answer, and may be considered to have settled a difficulty which has faced anatomists for three hundred years. The lymphatic sacs and capillaries have exactly the same relation to the tissue spaces as have the blood-capillaries. Both are foreign structures that grow into or invade the mesenchyme. Tissue spaces are no more a part of the lymphatic system than they are of the blood-vascular system. Thus, fluid within the veins should be called blood-serum, the fluid in the tissue spaces might be termed plasma, while the term lymph should be reserved for fluid within the lymphatics. The use of three distinct expressions as indicating three distinct elements would be a decided advantage. Von Recklinghausen's silver pictures show two different systems, the lymphatic vessels and the tissue spaces or lymph radicles. Melzer (1896 and 1911) has brought out well the physiological meaning of these distinctions.

In embryos before the formation of lymphatics, the mesenchyme varies greatly in different places, that is, it is considerably differentiated. In certain special constant places the meshes of the mesenchyme are very large, — for example, around the central nervous system. These spaces around the nervous system have especial significance in connection with the lymphatics, for these mesenchyme spaces, the anlage of the piarachnoid spaces, extend along the peripheral nerves in young embryos and have been confused with lymphatics.

Sections of human and other mammalian embryos will show spaces along the growing nerves, contracted at the origin of the nerves but widely expanded at the growing tips. These spaces may be termed perineural spaces.

In studying a long series of pig embryos injected into the piarachnoid space, it is found that often the injection mass runs out into the perineural spaces, thus outlining the peripheral nerves. Such injections do not enter true lymphatics, thus showing the independence of these two systems. In a study of the arachnoid made by the injection method in the Anatomical Laboratory of the Johns Hopkins University by L. L. Reford. and as yet unpublished, it has been shown that the thinning out of the mesenchyme around the central nervous system is not haphazard, but that injections of the same stage give the same pattern, and that the form of the arachnoid space changes as the brain develops. That is to say, the arachnoid space has as definite a form as the coelom and it never connects with the lymphatics. Moreover, no injections of lymphatics run over into the arachnoid or perineural spaces, showing that the great arachnoid and perineural space system is not a part of the lymphatic system.

Through the work of Budge (1880, 1887) there developed a theory that the coelom had a genetic relation or developed in common with the lymphatic system. He injected the extra-embryonal coelom in chick embryos, and found that the fluid passed out into the area vasculosa in forms simulating vessels and thought that this formed a primitive lymphatic system.

The finding that the lymphatic system arises from the veins, and that the tissue spaces and all the serous cavities of the body therefore stand in the same fundamental relation to the lymphatic system as they do to the blood-vascular system, marks a definite advance in our conception of the general morphology of the body, and is perhaps the most valuable result of the recent studies on the lymphatic system. This is as true for cavities like the various bursas and chambers in the eye as for the piarachnoid, the ccelom, the pleural and pericardial cavities.

Closely associated with the question of the relation of the lymphatics to tissue spaces are two points — namely, the question of growth of the lymphatic capillaries and the time-honored question of open and closed lymphatics — which are the most interesting of all problems associated with the structure of the lymphatic system.

The question of the growth of lymphatics is the crucial point in connection with the new theory. That the lymphatic capillaries and blood-capillaries grow by the same method was suggested by Kblliker as early as 1846 in a study of the living tadpole's tail. The matter could not be on a firm basis until after the important discovery that blood-vessels were lined by endothelial cells. The idea of the growth of blood-capillaries by sprouting had its earliest beginnings in the work of Schwann (1839), and involves a long series of observations in which the most telling are those on the living amphibian larva. That the growth of the lymphatic capillary, like that of the blood-capillary, is from the sprouting of their endothelial lining ceils was first discovered by Langer in 1S6S in a study of the tadpole's tail.

These observations, long unnoticed, were rediscovered by Ranvier (1S95-1S97) in a series of studies on amphibian and mammalian embryos. Ranvier saw that with this method of growth it was impossible to think of lymphatics starting as dilated tissue spaces and growing toward the centre. MacCallum (1902) was the next to call attention to this method of growth, and he added the observation, that, in watching the injection of these growing capillaries under the microscope, there were no lymph radicles connecting the lymphatics with the tissue spaces as seen in silver-nitrate specimens, but that the lymphatics had a complete wall and ruptured explosively under too great pressure, and were hence anatomically closed vessels. The lymph radicles are tissue spaces. Bartels (1909) has repeated the injections of MacCallum, and obtains the same figures of the long sprouts of endothelium ; he suggests, however, the theoretical objection to the theory growth of lymphatics by sprouting that this involves an idea of growth against the pressure of the fluid contained (pp. 46-47). This theoretical difficulty is not a real one, since it is possible to watch the lymphatics grow in the living form. The final proof that lymphatics grow by sprouting of their endothelium has been given by E. R. Clark (1909 and 1911), who watched the growth of a given lymphatic vessel in the same tadpole's tail under the high powers of the microscope for long periods of time. He describes, that, from the sides and ends of the growing vessels, long processes of protoplasm push out into new territory; these processes now advance, now, bend far out of their course to pick up some stray blood-corpuscles, and now retract entirely like long slender pseudopodia. Moreover, by subjecting the tadpole to lower temperatures, the activity of the endothelium can be checked, while under the stimulus of heat numerous tiny threads of protoplasm are pushed out, only a few of which grow into permanent lymphatics. Moreover, he has added an important discovery on the nature of the endothelium. He finds that the growing tip consists of a hyaline membrane, in which the nuclear areas, that is nuclei hidden by granular protoplasm, divide and move up and down the wall and out into the growing tips, even passing one another, so that the growing » tip is unquestionably a synecytium. This clears up one difficulty long associated with the idea of growth by sprouting — namely, whether endothelial strands were individual cells which subsequently became hollowed out. The tiniest vessels are hollow tubes of protoplasm. This discovery enlarges our conceptions of endothelium, especially in connection with Mollier's (1911) beautiful specimens showing the endothelium of the splenic veins in the form of a reticular protoplasmic syncytium.

Keibel Mall 2 513.jpg

Keibel Mall 2 514.jpg

Fig. 513. View of the blood-vessels and lymphatics (solid black) of a tadpole's tail (Hyla Pickeringii 10 mm. long). Fixation in Zenker's fluid. (After Clark, 1911.) The oblique lines represent the myotomes, and the numbers indicate the corresponding vessels of Fig. 514. Fig. 514. The same area as in Fig. 513. (After Clark, 1911.) Reconstruction from serial sections 10 m thick, stained with hsematoxylin and Van Gieson's mixture (acid fuchsin and picric acid), made by the use of an oil-immersion lens (Zeiss obj. 2 mm. and ocular 6).

It cannot be said that there is agreement among the recent workers on lymphatics. This "disagreement, we think, rests on a fact noted by His as far back as 1863, that " Eine nicht injizierte Lymphwurzelrohre zu erkennen, beinahe unmoglich ist." The lymphatic capillaries in early mammalian embryos seen in serial sections are conspicuously large in contrast with the blood-capillaries, but they are at the same time extremely irregular and the largest vessels are often connected by the tiniest threads of endothelium. In 1906 F. T. Lewis showed in rabbit embryos certain small isolated spaces arranged hi bead-like rows along the primitive veins extending out from the regions of the primitive sacs. These vessels are probably lymphatics; they are lined by true endothelium, are empty, and are larger than blood-capillaries. Their interpretation is given in Clark's figures 513 and 514. The study of these spaces, in their relation to the lymphatic system, resolves itself into an analysis of the limits of error of different methods. The three methods employed have been the study of the living by Clark, the study of serial sections of iminjected embryos -by Lewis, Huntington, and MeClure, and of injected embryos by myself. That the study of serial sections yields valuable results is unquestioned; the observations on the general distribution of the lymphatics in human ernbryos were made on such material. But in determining the essential point — namely, the method of growth of the lymphatic tip, whether by the addition of connective-tissue spaces, or by numerous venous anlages, or by the growth of its own endothelium — the method of the interpretation of sections fails, because the point at issue lies within the limits of error of the method.

The relative value of the method of iminjected and injected sections was in part tested in the skin of the embryo pig (Sabin, 190S), but the whole question has been much more conclusively tested by Clark (1911) in the tadpole's tail. His figures, two of which are copied, show the essential points. He first studied the entire lymphatic system as it can be seen in the living tadpole's tail. There is no question but that all of the lymphatics, to the last endothelial cell and protoplasmic sprout, can be seen. Moreover, the entire system so seen can be injected and nearly as much can be made out in a total specimen in alcohol. Such a specimen was drawn (Fig. 513). The tadpole was then sectioned and exactly the same area reconstructed. It was found, in the first place, that the amount which could be reconstructed varied greatly with the intensity of the stain.

With weak stains, like eosin or congo red, comparatively little could be seen, but an intense fuchsin stain gave the maximum advantage. By using a high dry lens (Zeiss 4 mm.) in specimens stained in fuchsin, both blood-capillaries and lymphatics split up into isolated islands or Lewis anlages. With the oil-immersion lens (Zeiss 2 mm.) more of the vascular and lymphatic systems could be reconstructed, but the isolated vessels were more distal, but still numerous, as seen in Fig. 514. This figure represents the maximum amount of blood-vessels and lymphatics that can be reconstructed in the tadpole's tail under the favorable conditions of knowing the extent of the lymphatics in the exact area and of intense protoplasmic stains. Clark regards this, and I think properly, as a crucial test of the relative value of methods.

The work of Huntington and McClure (1908-1910), presented for the most part in joint publications, advances a different idea in regard to the lymphatic system. Their position is a complicated one, for they hold that the lymphatic system arises by three different methods : first, that the jugular lymph-sacs are venous in origin; secondly, that some of the peripheral lymphatics are clefts between the endothelium of the veins and the surrounding mesenchyme, their socalled extra-intimal space theory; and thirdly, that some of the peripheral lymphatics arise as tissue spaces. In regard to the first point, they originally thought that the jugular lymph-sacs were extra-intimal (1906-08), but abandoned that idea in 1908. The extra-intimal theory is not a serious obstacle in connection with the lymphatic problem. Huntington and McClure find in specimens which have been fixed in Zenker's fluid, that the endothelium of the veins shrinks away from the surrounding tissue. This phenomenon they find more common in veins which are degenerating. In studying through a series of human embryos which show a great variation in the amount of maceration and in quality of fixation, we have found that such spaces vary according to the fixation. Moreover, in studying human embryos, it becomes clear that there are certain constant areas of unusually loose mesenchyme and these areas are the first to show the effects of maceration. In the living tadpole no extra-intimal spaces are to be seen, while in fixed specimens they are present. Thus the extra-intimal space is open to the charge of artefact, and, in order to be taken seriously, must at least first be shown to occur with all of the best fixatives. In connection with the lymphatics it can be shown that the growing lymphatic does not always follow the vein. Here it should be emphasized that the blood-capillaries lie in perfectly definite and constant areas, so that whether lymphatics actually replace them or not is readily tested. The lymphatic sacs do replace the veins; some at least of the peripheral lymphatics which McClure (1910) claims are extra-intimal do not replace veins, but exist beside them. Huntington and McClure show a tendency to abandon the extra-intimal theory in favor of the old theory of the connectivetissue origin of all the lymphatics save the jugular lymph-sacs. The theory that lymphatics grow by the addition of tissue spaces rests on the observations of sections. The appearances in sections remain open to a variety of interpretations, in contrast with the simplicity and sharpness of the appearances in the living form. Therefore for the theory that the lymph-vessels develop otherwise than by the sprouting of the endothelium of preceding vessels we have no sufficient proof.

  1. Many of the facts concerning the development of the lymphatic vessels in human embryos have been obtained from the study of the Mall collection.
  2. The fact that until very recently the weight of evidence rested on the side of the theory that the lymphatic system arose from tissue spaces will be shown in the following quotation from the last — that is, the 6th — edition of Kollikei-'s Geweblehre, 1902, page 681, " Ranvier glaubt daher, dass die Lymphgefasse vom Venensy stern nach der Peripherie in ahnlicher Weise durch Sprossung fortwachen, wie eine Druse mit verzweigtem Gangssysteme von einer Schleimlianti-ohre aus . . . Die Aufstellungen Ranvier's sind keineswegs sicher erwiesen und stehen im Gegentheile in Widersprueh mit den anderen gefundenen Tatsachen ; sie wurden jedoch hier angef uhrt, weil durch dieselben der Vorstellung von der ganzlichen Vershiedenheit von Bindegewebespalten und echten Lymphgefiitsen der scharfste Ausdruch gegeben wirt." Ranvier's comparison of the growth of the lymphatic system to the growth of a gland seems an unfortunate one, since the truer and more obvious comparison of the growth of lymphatic capillaries to blood capillaries, both invading by the same method, is thereby lost sight of. The second point brought out by Von Ebner, that, should the new theory prevail, it would lead to the sharpest possible separation of the lymphatics and the tissue spaces from the anatomical stand-point, is exactly what has happened.
  3. This origin of the subclavian sac in human embryos as an extension of the jugular sac is interesting in connection with F. T. Lewis's (1906) discovery, that in rabbits the subclavian sac arises independently from the veins.
  4. In this connection it is interesting to note, that in the amphibia the pulsating lymph-hearts have exactly the same relation to the peripheral vessels as the sacs in mammals have to the corresponding vessels. Thus the sacs and primary lymph-glands represent the amphibian lymph-hearts.
  5. This idea finds a very interesting' confirmation in the work of Jolly (1910) on the lymph-giands of birds, for he finds that the first lymph-glands, the jugular and ischiatic groups, are centrally placed, and thus support Ranvier s theory of the growth of lymphatics from centre to periphery.
  6. The development of lymph-nodes has been followed in a number of recent papers by Saxer (1896), Gulland (1894), Kollmann (1900), Kling (1904), Sabin (1905 and 1909), and Jolly (1910), of which Kling and Sabin refer to human embryos.


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Baetjer, W. A. : On the origin of the Mesenteric Sac and Thoracic Duct in the Embryo Pig. Amer. Jour, of Anat. Vol. 8. 1908.

Bartels, P. : Das Lymphgef asssystern, in Bardeleben's Handbuch der Anatomie des Meusehen. 1909.

Bichat : Anatomie generale. Paris, 1801. Breschet: Le systenie lymphatique. p. 185. 1836.

Budge: Ueber ein Kanalsystem im Mesoderm vou Hiihnerenibryonen. Arcb. f. Anat. u. Pbys. Anat. Abt. 1880. Untersuebungen iiber die Entwicklung des Lympbsystems beim Hiihnerembryo. Ebenda. 1S87.

Chievitz: Zur Anatomie einiger Lympbdriisen im erwaebsenen imd fetalen Zustande. Arcb. f. Anat. u. Pbys. Anat. Abt. 1881. He describes the mesenteric glands in tbe buman embryo.

Clark, E. R. : Observations on Living, Growing Lymphatics in the Tail of the Frog Larva. Anat. Record. Vol. 3. 1909. On the Inadequacy of the Method of Reconstruction in Studying Developing Lymphatics. Anat. Record. Vol. 5. 1911.

Conil, C. E. J.: Contribution a l'etude du developpement des ganglions lymphatiques. These de Bordeaux. 1890. Engel: Ueber den Bau und die Entwicklung der Lymphdrusen. Prager Vierteljahrsschrift. Bd. 2. 1850.

Evans, H. M. : On the Occurrence of Newly-formed Lymphatic Vessels in Malignant Growths. Johns Hopkins Bulletin. Vol. 19. 1908. Gulland: The Development of Lymphatic Glands. Journ. of Path, and Bact. Vol. 2. 1894. Gives an excellent review of the literature. Rep. from the Labor, of the R. College of Physicians. Edinburgh. Vol. 5. 1896.

Heuer, G. J. : The Development of the Lymphatics in the Small Intestine of the Pig. Amer. Journ. of Anat. Vol. 9. 1909.

His, W. : Ueber die Wurzeln der Lymphgef asse in den Hauten des Korpers und iiber die Theorien der Lymphbildung. Zeitschr. f . wiss. Zool. Bd. 12. 1863. Ueber das Epitbel der Lymphgefasswurzeln und iiber die von Recklinghausen'schen Saftkanalchen. Zeitsch. f. wiss. Zool. Bd. 13. 1863 2 .

Hoyer: Ein Beitrag zur Histologie bindegewebiger Gebilde. Arch. f. Anat. u. Pbys. u. wissenschaftl. Medizin. 1865.

Huntington GS. The genetic interpretation of the development of the mammalian lymphatic system. (1908) Anat. Rec. 2: 19-45.

Huntington : The Genetic Interpretation of the Development of the Mammalian Lymphatic System. Anat. Record. Vol. 2. 1908. The Phylogenetic Relations of the Lymphatic and Blood-vascular Systems in Vertebrates. Anat. Record. Vol. 4, p. 1. 1910. The Genetic Principles of the Development of the Systemic Lymphatic Vessels in tbe Mammalian Embryo. Anat. Record. Vol. 4, p. 399. 1910.

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The Anatomy and Development of the Jugular Lymph-sacs in the Domestic Cat. Anat. Record, yol. 2. 1908.
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Ingalls NW. A contribution to the embryology of the liver and vascular system in man. (1908) Anat. Rec. 2: 338–344.

Jolly, J. : Recherches sur les ganglions lymphatiques des oiseaux. Arch. d'Anat. Microsc. T. 11. 1910. Gives a complete bibliography of Ranvieris works.

Kling: Studien iiber die Entwicklung der Lymphdrusen beim Menschen. Upsala Lakareforenings Forhanslhiger. 1903 and Arch. f. mikr. Anat. u. Entwicklnngsgesch. Bd. 63. 1904.

Knower, H. McE. : The Origin and Development of the Anterior and Lymphhearts and Subcutaneous Lymph-sacs in the Frog. Anat. Record. Vol. 2. 1908.

Kolliker: Hist ologisc he Studien an Batrachierlarven. Zeitsehr. f. wiss. Zool. Bd. 43. Annales des sciences natnrelles. Serie 3. T. 6. 1846. Handbuch der Gewebelehre des Menschen. 1902.

Kolljian : Die Entwicklung der Lymphkndtcken in dem Blinddarm und in dem processus veriniforrnis. Die Entwicklnng der Tonsillen und die Entwicklung der Milz. Arch. f. Anat. u. Pkys. Anat. Abt. 1900. Labeda: Systeme lymphatique : Cours du chyle et de la lymphe. 186(3. Laxger: Ueber das Lymphgefasssystem des Froscbes. Sitzl. d. k. Akad. d.

Wissenseh. Bd/55, 1867, and Bd. 58, 1868. Lauth: Essai sur vaisseaux lyinphatiques. These de Strasbourg. 1824.

Lewis, F. T. : The Development of the Vena Cava Inferior. Amer. Jour, of Anat. Vol. I. 1901-1902.

Lewis FT. The Development of the Lymphatic System in Rabbits. Amer. Jour, of Anat. Vol.5. 1906.

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The Extra-intimal Theory of the Development of the Mesenteric Lymphatics in the Domestic Cat. Verhandl. d. Anat. Gesellsch. Erg. Heft. z. Anat. Anz. Bd. 37. 1910.

McClure and Silvester: A Comparative Study of the Lymphatico-venous Communications in Adult Animals. Anat. Record. Vol. 3. 1909.

Melzer and Adler: Experimental Contribution to the Study of the Paths by which Fluids are carried from the Peritoneal Cavity into the Circulation. Jour. Exp. Med. Vol. I. 1896.

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Meyer, A. W. : The Haemolymph Glands in Sheep. Anat. Record. Vol. 2. 1908. Mierzejewskl, L. : Beitrag zur Entwicklung des Lymphgefasssystem der Vogel. Bull. d. l'Acad. d. Sciences d. Cracovie. 1909.

Nuck, A.: Adenographia curiosa. Leidae. 1691.

Orth : TJntersuchungen iiber Lymphdriisenentwieklung. Dissertation. Bonn. 1870. According to Chievitz, Orth confused the sympathetic ganglia with the lymphatic glands. Peksa: Studio sulla morfologia e sulla topografia della cisterna chili e del ductus thoracicus. Lab. di Anat. norm, della Univ. di Roma. T. 14. 1908-1909.

Polinski, W. : Untersuchungen iiber die Entwicklung der subcutanan Lymphgefasse der Sauger, in Sonderheit des Rindes. Bull. d. FAcad. d. Sciences d. Cracovie. 1910.

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Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

XVIII. Development of Blood, Vascular System and Spleen: Introduction | Origin of the Angioblast and Development of the Blood | Development of the Heart | The Development of the Vascular System | General | Special Development of the Blood-vessels | Origin of the Blood-vascular System | Blood-vascular System in Series of Human Embryos | Arteries | Veins | Development of the Lymphatic System | Development of the Spleen
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