Paper - A case of atresia of the esophagus combined with traoheoesophageal fistula in a 9 mm human embryo, and its embryological explanation

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Gruenwald P. A case of atresia of the esophagus combined with traoheoesophageal fistula in a 9 mm human embryo, and its embryological explanation. (1940) 293-302.

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A Case of Atresia of the Esophagus Combined with Traoheoesophageal Fistula in a 9 mm Human Embryo, and its Embryological Explanation

Peter Gruenwald Department Of Anatomy, Chicago Medical School

Three Figures

  • This work was aided by a grant from the Emergency Committee in Aid of Displaced Foreign Medical Scientists.


One of the most frequent malformations of esophagus and trachea is atresia of the esophagus combined with tracheocsophageal fistula. The great number and the almost identical appearance of the reported cases show that it is at typical malformation and we should therefore be able to find an embryological explanation of its genesis.

It is a well—established fact that malformations can be divided in two groups: typical and atypical forms (Politzer and Sternberg, ’29). Provided a sufi‘icient number of cases are observed, the former are characterized by the fact that many identical specimens can be found, and furthermore by the presence of a continuous series of forms ranging from lower to higher degrees of abnormality. The origin of these malformations can be explained by different degrees of disturbance of certain developmental processes. In contrast to this, the atypical malformations are irregular and, apart from incidental similarities, different from each other. They cannot be arranged in a series according to the degree of disturbance of certain developmental processes, but arise from causes of incalculable effect such as amniotic adhesions. Good examples of both types can, according to Politzer (’37), be found among the clefts of the face, where the typical malformations are represented by the harelip, and the atypical ones by the oblique clefts.

Returning to the malformation to be discussed here, we find that no satisfactory explanation of its genesis has been offered in spite of many efforts. Therefore, the description of a case in a young human embryo and a consideration of the processes participating in early development of esophagus and trachea may be of interest.

The malformation was found in an externally normal 9-mm. human embryo, associated with agenesis of both ureteric buds and hypoplasia of the right umbilical artery. Both other malformations have been described previously (’39), at a time when the anomaly of the esophagus had not yet been discovered. The embryo was fixed in Bouin’s solution, embedded in paralfin and sectioned serially (8 u) in transverse direction. Azan stain was used on all sections. In order to demonstrate the abnormal condition of trachea and esophagus, a reconstruction of a midsagittal section of these organs was made at an enlargement of 100 X (fig. 1). It shows. the trachea separating from the esophagus in the normal way (fig. 2 a) and about 140 u caudad a blind ending of the esophagus. About 400 u below the prospective aditus ad laryngem (260 11 below the blind end of the upper part of the esophagus), the lower part of the esophagus branches from the trachea, at a point about 630 p above the bifurcation (fig. 2 b). Near its origin from the trachea the esophagus has a very narrow portion (fig. 2 c), which is followed by a dilatation at the level of the bifurcation (fig. 2 d). From there on the esophagus can be traced to the stomach without further peculiarities.

The findings in this embryo correspond exactly to the condition of the great number of cases observed in newborns. The latter resemble each other very closely; the only difference concerns the level of the communication between the trachea and the lower portion of the esophagus. Our case seems to show a rather high site of the fistula, but a difference in growth between the parts cranial and caudal to the fistula might have resulted in a change of this site, had the embryo been able to live longer. However, differences in the level of the fistula comparable to those found in newborns, already exist in this early stage. This can be demonstrated by a comparison. of our embryo with another case of similar age described by Ysander (’24). This is an 8—mm. thoracopagus and botl:1 partners show an atresia of the esophagus and its lower portion originating from the bifurcation as the straight continuation of the trachea. In our embryo, in eontradistinction, the fistula opens into the laryngo-tracheal tube almost as high as its upper third. In both cases the essential features of the malformation including an individual difference in the level of the fistula are already established. Lewis (’12) briefly mentions having seen a similar malformation in an 18.1-mm. embryo of the Harvard Collection. One more case was found by Yamasaki (’33) in an 8.5—mm. embryo with multiple malformations. In this case, however, the malformation of the esophagus is “atypical” since the fistula is interrupted, too. Its cranial remnant was found as a divertieulum of the posterior aspect of the bifurcation of the trachea, pointing in the direction of the blind upper end of the caudal part of the esophagus.

Fig.1 Mid-sagittal reconstruction of esophagus and respiratory tract of the maldeveloped embryo. Magnification X 67. e, esophagus; s, stomach; t, laryngetracheal tube. The lungs (1, r) are projected on the plane of reconstruction.

Fig.2 Outlines of the epithelium of esophagus and laryngo-tracheal tube of the same embryo, as appearing in the cross sections, indicated by arrows in figure 1. Same magnification.

The condition under consideration is doubtless an independent malformation in regard to other anomalies and it is unjustified to make other malformations responsible for its genesis. However, in a high percentage, it is combined with malformations of other organs, as in our case with anomalies of the kidneys and the right umbilical artery and in Ysander’s case with a thoracopagic condition. Most of the publications concerning newborns also report other anomalies, especially of kidneys, rectum and cardiovascular system. I had an opportunity to investigate all malformations observed in the Pathology Department of the Cook County Hospital in Chicago (Grruenwald, in press), and two cases of the anomaly in question were observed during a 10-month period. In one specimen a defect of the interatrial septum and unilateral hydroureter were found in addition to the anomaly of the esophagus, and in the other one there was an unsymmetrical, fused kidney and atresia of the anus with a recto-vaginal fistula. It is obvious that none of these concomitant malformations is in a direct developmental relation to the anomaly of the esophagus ; only genetic factors can be responsible for the coincidence.

In 1931, Rosenthal described eight cases of atresia of the esophagus combined with tracheo—esophageal fistula. He also reviewed the theories proposed for the explanation of the genesis of this malformation and came to the conclusion that none of them is satisfactory. He proposed a new explanation, based on a comparison with the genesis of myeloschisis. He emphasized that the separation of the respiratory anlage from the esophagus is not due to the surrounding mesenchyme pushing the lateral walls of the common tube mesad, but to a process performed actively by the entoderm itself. Should this process fail, the result would be a tracheo—esophageal fistula. This however, does not explain the atresia of the esophagus and Rosenthal had to assume another abnormal condition to explain this part of the malformation. He makes responsible “the deficiency in the dorsal entodermal cells,” without explaining how this deficiency is to be understood. I believe that the constant combination of atresia and flstula is the outstanding feature of this malformation and any theory has to explain this coincidence. Therefore, I cannot consider Rosenthal’s explanation satisfactory, as much as I agree with his criticism of the other theories.

In the following, a new explanation will be offered for the genesis of the malformation in question. It will be shown that a mere disturbance of the coordination of normal developmental processes can account fully for the combination of atresia of the esophagus and tracheo—esophageal fistula.

A review of early development of the respiratory tract reveals that two processes are of great importance after the primordium has reached the stage of a diverticulum of the fore-gut. One of them is the separation of the respiratory anlage from the gut; it proceeds in caudo-cranial direction until only the upper part of the original communication persists to form the aditus ad laryngem. The other process consists of a rapid growth in the caudal direction of the laryngetracheal tube. This results not only in an absolute lengthening corresponding to that of the entire body region, including the esophagus, but also in a relative increase in length compared with the surrounding structures. It is important to notice that at this time the laryngo-tracheal tube grows faster than the esophagus, because this difference in the growth rates of both tubes can lead to normal development only if it is preceded by the separation of both primordia already mentioned. If not, both anlagen will interfere with each other according to their different growth intensity. This leads, according to the theory to be proposed here, to a malformation because the esophagus, being still attached to the faster growing laryngetracheal tube, is drawn out by the latter. Its contribution to the undivided tube is smaller compared with the rapidly growing trachea. Figure 3 will help to explain this process. Diagram (1 shows an early stage prior to separation and lengthening of the respiratory anlage; diagram 1) shows the condition after these two processes have taken place in normal order. The consequence of a complete failure of separation of the trachea is shown i11 diagram d. The rapidly growing trachea has by its faster growth transformed the corresponding part of the esophagus into a narrow strip of tissue participating in the formation of its own dorsal wall. From the end of this composite tube originates the normal caudal part of the esophagus, corresponding to the portion of the anlage that had been caudal to the respiratory diverticulum in stage a. The result of this development is an atresia of the esophagus and a tracheo-esophageal fistula, representing the condition to be explained here. The development in cases with an incomplete separation of the trachea from the esophagus is shown in the diagram of figure 3 c; it results in a similar malformation, with the fistula at a higher level. This would be the genesis of the malformation of our case.

Fig. 3 Diagrams of the development of laryngo-tracheal tube (t) and esophagus (e), after normal and abnormal separation; p, pharynx. a, early stage, normal; b, later stage after normal separation of both anlagen; c, corresponding stage after incomplete separation; (1, corresponding stage after complete failure of separation. In c and d, the fast growing laryngo-tracheal tube has drawn out the unseparated portion of the esophagus into part of its own dorsal’ wall.

Consequently, different degrees of failure of separation lead to a continuous series of different forms of the malformation; the higher the degree of abnormal development the more caudal opens the esophagus into the trachea. The question arises now, why we always find the fistula in the lower part of the trachea and never in its upper levels or in the larynx. In low degrees of anomaly, when the esophagus is not much drawn out, a later continuation of the separation can probably lead to the establishment of a normal condition; moreover, the fistula may be shifted caudad later by a comparatively faster growth of the cranial portion of the trachea, as mentioned before. This assumption is supported by the fact that in the early stage described here, the fistula opens into the trachea at a higher level than it is ever found in newborns.

Many authors have referred before to a. failure of separation of the trachea from the esophagus as the cause of the malformation in question. The difliculties arose when it came to explaining satisfactorily both atresia and fistula of the esophagus on a common basis. I think that the consideration of differences in growth as proposed here, will help to overcome this difiiculty and reach a satisfactory solution of our problem.

A few details remain to be explained, above all the origin of the upper atretic part of the esophagus. We have to assume that it develops from that part of the primordium which remains attached to the pharynx during the development of the malformation. This part probably grows eaudad secondarily, perhaps in an attempt of regulation. It will be evident from a comparison of figure 3 c and d that the site of the fistula has no bearing on the length of the upper part of the esophagus, as it is the fact. This upper part may even reach farther down than the fistula (see Fischer, ’26), which shows its independent growth.

Another point is the fate of the supposed strip of esophageal tissue in the dorsal wall of the trachea cranial to the fistula. Even if our theory is correct, we do not necessarily have to find esophageal structures again in late stages, since we know that many developing structures have a tendency to form a complete and normal organ and that the other intercalated tissues, as, e.g., grafts may be transformed in order to reach this purpose (as far as their potencies allow such transformation). In the same way the tracheal anlage may transform the esophageal tissue into a part of its own. However, we know that at least in a part of the cases esophageal structures such as squamous epithelium or striated muscle actually occur in the dorsal wall of the trachea as a continuation of the esophagus craniad from the fistula (Gutmann, ’12; Konopacki, ’12; Ladwig, ’20). Rosenthal’s case 1 is also in favor of this theory. The description reads: “The pharynx led into a widely dilated esophagus, which was completely closed at a point 1 cm. above the bifurcation of the trachea. From this point on, the esophagus was nonexistent as a patent tube, but continued as a ridge in the form of a longitudinal thickening on the posterior wall of the trachea. It continued in this fashion to a point a little above the bifurcation of the trachea, where it once more emerged as a patent tube.” It seems that the esophageal strip was even grossly visible in this newborn. No histological examination was reported.

In conclusion, we see that the genesis of the entire complex of the malformation under consideration can be explained by the assumption of a more or less complete failure of the laryngo—tracheal tube to separate in proper time from the esophagus. This explains the fistula, and the atresia is a sequel of the fast growth of the trachea drawing out the corresponding part of the esophagus into a narrow strip contributing to its own dorsal wall. The anlage of the trachea may influence this strip to change into tracheal structures; however, in some cases the unchanged esophageal tissues remain apparent.


  1. The typical combination of atresia of the esophagus and tracheo—esophageal fistula was found in a 9-mm. human embryo. The principal features of the malformation are already established in this early stage. The fistula opens into the upper half of the laryngo-tracheal tube.
  2. A review of the early development of the respiratory tract shows that its separation from the esophagus is closely followed by a rapid growth of the laryngo-tracheal tube. It is believed that the malformation in question develops if the lengthening occurs before the separation is completed.
  3. The diflerent degrees of this malformation (fistula at different levels of the trachea) develop according to the degree of separation occurring prior to the onset of rapid growth. The opening of the lower portion of the esophagus into the bifurcation represents the highest degree of anomaly.
  4. The length of the upper part of the esophagus is independent of the level of the fistula.

Literature Cited

FISCHER, W. 1926 Speiserohre. In: Handbuch der speziellen pathologisehen

Anatomic und Histologie, vol. IV/ 1, pp. 74-165.

GRUENWALD, P. 1939 The mechanism of kidney development in human embryos as revealed by an early stage in the agenesis of the ureteric buds. Anat. Rec., vol. 75, pp. 237-247.

1940 A survey of congenital anomalies as found in 1131 neeropsies. Illinois Medical Journal. (In press.)

GUTMANN, S. 1912 Ueber einen Fall von Oesophagusatresie und Oesophagotrachealfistel, kombiniert mit Missbildungen am Herzen und an den grossen Gefiiissen. Frankf. Zeitschr. f. Patho1., vol. 9, pp. 459-469.

KONOPACKI, M. 1912 Ueber einen Fall Von angeborenem partiellen Speiseriihrendefekt (Atresia. oesophagi) als Beitrag zur Entwicklnng der Luftriihre beim Menschen. Zentralbl. f. Pathol., vol. 23, pp. 386-394.

LADWIG, A. 1920 Ein bemerkenswerter Fall von Missbildung des OesophageoTrachealrohres, zugleich ein Beitrag zur Auffassung Von der formalen Genese derartiger Missbildungen. Zentralbl. f. Pathol., vol. 31, pp. 613-616.

LEWIS, F. T. 1912 The development of the oesophagus. In: Keibel and Mall, Manual of human embryology, vol. 2, pp. 355-368. J. B. Lippincott 00., Philadelphia.

POLITZER, G. 1937 Neue Untersuchungen fiber die Entstehung der Gesichtsspalten. Monschr. f. Ohrenhei1k.,. vol. 71, pp. 63—73.

POLITZER, Gr., AND H. STERNBERG 1929 Ueber einen missbildeten menschlichen Embryo des ersten Monates. Frankf. Zeitschr. f. Patho1., vol. 37, pp. 174-210.

ROSENTHAL, A. H. 1931 Congenital atresia of the esophagus with tracheo~ esophageal fistula. Arch. of Path0l., vol. 12, pp. 756-772.

YAMASAKI, M. 1933 Ein menschlicher Embryo von 8.5 mm. Scheite1—Steissl5£u1ge mit fehlerhaften und ungewiihnlichen Bildungen. Arb. a. d. anat. Inst. Kais. Jap. Univ. Sendai, vol. 15, pp. 27-59.

YSANDER, F. 1924 Studies on the morphology and morphogenesis of human thoracopagic monsters. Inaug.-diss. Upsala.

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