- Email: [email protected]
Embryology and Pathology of Branchial Cleft Cysts
SYlnposium on Surgical Leswns of the Neck and Upper Mediastinum
Embryology and Pathology of Branchial Cleft Cysts SAMUEL P. HICKS
cleft cysts are moderately frequent lesions that are present most often in the anterior and lateral parts of the external neck. They attract attention 'by becoming infected, by filling with secretions, or the lymphoid tissue in them may enlarge. Occasionally they occur as frank fistulas to the pharynx. The name, branchial cleft cyst, or simply, branchial cyst, is an arbitrary one, but no better term except possibly the noncommittal "cyst of the neck" seems to be available. The origin and embryologic implications of these lesions have excited spirited discussion and elaborate theories for over a half century.1-9 In the early weeks of development there is a close relation between the pharynx within and the outer tissue arches that grow forward to form the face and neck, and this close proximity of the pharynx and its anlagen for neck organs to the overlying integument offers many possibilities for maldevelopment. Perhaps the most thorough and enthusiastic study of the embryology of the neck and the origin of branchial cysts was that of Wenglowski early in this century. He reconstructed models from more than 60 human embryos and concluded that branchial cysts took their origin in the course of the thymus as it grew down in the neck as a tube from the third pharyngeal pouch. However, the absence of unequivocal thymus BRANCHIAL
619
620
Samuel P. Hicks
tissue in most. hranchial cysts, and the course of a few cysts that run from the tonsillar region to the lower neck are the most convincing reasons for not accepting Wenglowski's theory without reservations. The development of the neck region in the human being is essentially as follows: Between the third and seventh weeks of life the major structures of the face and neck are laid down and rapidly develop into a
",HMC
(EAR)
Fig. 139. Huma.n embryo development from about two to seven weeks (ca. 2 to 20 mm.) to show schematically the branchial clefts. The hyomandibular cleft (HMC) is a convenient landmark and separates the first or mandibular arch from the second or hyoid arch. It is also the first cleft (I) and is opposite the first pouch. Later these structures correspond to the ear and eustachian tube. The derivatives of the other pouches are noted in the text. (M = mandibular arch which becomes the maxilla and the mandible. H = hyoid or second arch. I, II, III, IV = branchial clefts. CS = cervical sinus or receding clefts III and IV.) (Based on Patten, Kingsbury, and Harvard Embryological Collection.)
form closely resembling the adult configuration (Fig. 139). The gut tube, closed at first, opens as a mouth and coincidently paired lateral thickenings in the region of the head and future neck appear. These thickenings take the form of arches and grow toward the midline anteriorly. Separating these arches are fissures or clefts. Because these arches and clefts remind embryologists of the developing gills of fish and amphibians they have been called branchial arches and branchial clefts (branchia, Greek for gills).
Branchial Cleft Cysts
821
At the time these arches are developing, the pharynx is also actively growing. It becomes a somewhat flattened tube curved toward the front and from its lateral wall a series of four pouches protrude (Fig. 140). These internal pouches of the pharynx come in contact with the corresponding outside clefts along the most lateral aspect of the neck. Only a single cell layer may separate the pharynx from the outside at this stage as shown in Figure 141. • A glance at the embryo during these stages of development in Figures 139 and 140 is sufficient to show that all sorts of possibilities present themselves for errors of fusions of the parts that make up the face and neck and pharynx. It is, therefore, quite reasonable to assume that the
I
--Nne
(I)
Fig. 140. Relations of pharyngeal pouches to branchial clefts in a fiye weeks' embryo. The pharynx is shown schematically in heavy black outline. (T = medial thyroid anlage. L = lung bud.)
c
cysts of the neck have their origin in embryologic errors related to these growth processes. The finding of lymphoid tissue associated with squamous and other epithelium, that remind one of pharyngeal and tonsillar tissues, in so many branchial cysts is also suggestive of their origin in a junction of cleft and pouch. However, some of these cysts have no lymphoid tissue and become filled with desquamated keratin and are histologically indistinguishable from epidermal inclusion cysts. The primitive pharynx gives rise to a number of structures of interest in connection with branchial cysts, including components of the thyroid, the parathyroid glands, thymus gland, mucous glands, lymphoid (ton~ siHar) tissue, the eustachian tubes and middle ear chamber (Figs. 139 and 140). The highest or first pharyngeal pouch corresponds to and is in contact with the hyomandibular cleft (HMC) between the mandibular (M) and hyoid (H) arches; the pouch forms the eustachian apparatus
622
Samuel P. Hicks
and the cleft later corresponds to the ear and to the "line" of the lower jaw. The second pouch will correspond to the supratonsillar fossa region, and from the epithelium of the third develop the thymus and upper pair of parathyroid glands (also known as parathyroid III or parathymus). The fourth pouches are the origin of the lower pair of parathyroids
Fig. 141. Human embryo, horizontal section, 7.5 mm., about five weeks. The scant separation of pouches from clefts is evident. This would correspond to a horizontal section through the right hand member of Figure 140. (Embryo 256, Harvard Embryological Collection, courtesy Dr. George B. Wislocki, Professor of Anatomy.)
(parathyroid IV) and contribute tissue to the thyroid proper. As the lower clefts recede they form the cervical sinus which marks the future lower border of the neck. It should not be surprising, then, that branchial cysts may contain tissue whose anlagen arose from pharyngeal epithelium or other structures originating in the neck region. That the thymus should have attracted Wenglowski's attention as a prime source of neck cysts is illustrated in Figure 142 where the extended course of the thymus is
623
Branchial Cleft Cysts
shown in an embryo 19 mm. in length. Here, of course, this organ and the other pharyngeal derivatives are by now fairly well differentiated. Thymus tissue is said to occur occasionally in branchial cysts. In 100 reviewed (Table 1) for histologic characteristics in this laboratory, * no
Fig. 142. Human embryo, frontal section, 19 mm., about twenty weeks. The extent of the thymus, the thyroid and parathyroids is shown. (Embryo 828, Harvard Embryological Collection, courtesy Dr. George B. Wislocki, Professor of Anatomy.)
Table 1 HISTOLOGIC CHARACTERISTICS SEEN IN
100
Lymphoid tissue" .. " Squamous epithelium .. " . Other epithelium or closely associated glands .... " Thymus ..... " " " . " " " " " Thyroid" " . " . " " " " " " " " " " " Parathyroid. " " " " "
BRANCHIAL CYSTS
91 98 10
o
o 1
* Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts.
624
Samuel P. Hicks
unequivocal thymus tissue was seen, but one cyst did have a small parathyroid gland in its wall. In the cases reviewed, mucous glands were occasionally present in close association with the cyst. Thyroid tissue was not seen in a cyst wall, but two lesions were closely associated with the thyroid gland. There are two reasons why the presence of thyroid tissue may be a rare occurrence in branchial cysts. The first is that the pathologist would probably call such a lesion a thyroglossal cyst even if it were not quite in the midline. The other is that although the fourth pouch is incorpo-
Fig. 143. Branchial cysts. The squamous epithelium and lymphoid tissue are frequent findings, the mucous epithelium is less often seen (hematoxylin and eosin, X125). (This illustration reduced approximately 60 per cent of original photomicrograph.)
rated into the development of the thyroid, it may be .inherently less likely to be involved in errors leading to cysts. The finding of mucous glands could be attributed to an abnormal embryologic origin in some cases in which they are clearly out of place. However, in deeply or highly situated lesions the relations of these appendages might be less certain. Figure 143 shows histologic patterns that may be found in branchial cysts. It is popular to think of developmental deformities as following a rigid and predictable pattern. Actually, this is not true in medical practice. Some deformities in man and animals that are clearly due to a genetic fault-an "abnormal chromosome" in the germ cell-do follow a fairly stereotyped pattern. The developmental chemistry of the embryo is
626
Branchial Cleft Cysts
predetermined by the germ plasm, so to speak, and at a certain stage morphogenesis departs from its usual course. Other nongenetic deformities-are the result of accidents during development, that is, they are due to extrinsic forces acting on the organism during growth. Although these may mimic genetic abnormalities they are largely unpredictable, because the time and the nature of the injurious agent are not known (except in experimental embryologyB). Whether branchial cysts in man .are genetic or accidental in origin is . not known. They are classed as a disease entity, but they comprise quite a variety of patterns that must have arisen in different sites and at different periods of early embryonic development. Of what value, then, is any sort of embryologic study that tries to explain branchial cysts? There are two practical results of such studies. One is that the surgeon may anticipate that these cysts will range from relatively simple lesions to fairly complex fistulas that may involve a number of neck structures, even the pharynx. The other is that both the surgeon and the pathologist can expect to find a variety of tissues in these lesions as their embryologic origin so clearly indicates.
•
REFERENCES 1. Bailey, H.: Clinical aspects of branchial fistulae. Brit. J. Surg. 21: 173-182 (Oct.) 1933. 2. Gill, N. W.: A branchial fistula terminating in a tubulo-dermoid cyst lying posterior to the tonsil. J. Laryng. & Otol. 64: 62-69 (Feb.) 1950. 3. Hicks, S. P.: Developmental manifestations produced by radiation. Am. J. Roentgenol. 69: 272-293 (Feb.) 1953. 4. Kingsbury, B. F.: The development of the human pharynx. I. The pharyngeal derivatives. Am. J. Anat. 18: 329-397, 1915. 5. Meyer, H. W.: Congenital cysts and fistulae of the neck. Ann. Surg. 95: 1 (Jan.); 226 (Feb.) 1932. 6. Patten, B. M.: Human embryology. Philadelphia, Blakiston, 1946, 776 pp. 7. Rabl, C.: II. Zur Bildungsgeschichte des Halses. Prager med. Wchnschr. 12: 3, 1887. 8. Weller, G. L.: Development of the thyroid, parathyroid and thymus glands in man. Contributions to embryology, Carnegie Institute of Washington, No. 141, vol. 24, 1933. 9. Wenglowski, R.: ttber die Halsfisteln und Cysten. Arch. f. klin. Chir. 100: 789-892, 1913.
Embryology and Pathology of Branchial Cleft Cysts SAMUEL P. HICKS
cleft cysts are moderately frequent lesions that are present most often in the anterior and lateral parts of the external neck. They attract attention 'by becoming infected, by filling with secretions, or the lymphoid tissue in them may enlarge. Occasionally they occur as frank fistulas to the pharynx. The name, branchial cleft cyst, or simply, branchial cyst, is an arbitrary one, but no better term except possibly the noncommittal "cyst of the neck" seems to be available. The origin and embryologic implications of these lesions have excited spirited discussion and elaborate theories for over a half century.1-9 In the early weeks of development there is a close relation between the pharynx within and the outer tissue arches that grow forward to form the face and neck, and this close proximity of the pharynx and its anlagen for neck organs to the overlying integument offers many possibilities for maldevelopment. Perhaps the most thorough and enthusiastic study of the embryology of the neck and the origin of branchial cysts was that of Wenglowski early in this century. He reconstructed models from more than 60 human embryos and concluded that branchial cysts took their origin in the course of the thymus as it grew down in the neck as a tube from the third pharyngeal pouch. However, the absence of unequivocal thymus BRANCHIAL
619
620
Samuel P. Hicks
tissue in most. hranchial cysts, and the course of a few cysts that run from the tonsillar region to the lower neck are the most convincing reasons for not accepting Wenglowski's theory without reservations. The development of the neck region in the human being is essentially as follows: Between the third and seventh weeks of life the major structures of the face and neck are laid down and rapidly develop into a
",HMC
(EAR)
Fig. 139. Huma.n embryo development from about two to seven weeks (ca. 2 to 20 mm.) to show schematically the branchial clefts. The hyomandibular cleft (HMC) is a convenient landmark and separates the first or mandibular arch from the second or hyoid arch. It is also the first cleft (I) and is opposite the first pouch. Later these structures correspond to the ear and eustachian tube. The derivatives of the other pouches are noted in the text. (M = mandibular arch which becomes the maxilla and the mandible. H = hyoid or second arch. I, II, III, IV = branchial clefts. CS = cervical sinus or receding clefts III and IV.) (Based on Patten, Kingsbury, and Harvard Embryological Collection.)
form closely resembling the adult configuration (Fig. 139). The gut tube, closed at first, opens as a mouth and coincidently paired lateral thickenings in the region of the head and future neck appear. These thickenings take the form of arches and grow toward the midline anteriorly. Separating these arches are fissures or clefts. Because these arches and clefts remind embryologists of the developing gills of fish and amphibians they have been called branchial arches and branchial clefts (branchia, Greek for gills).
Branchial Cleft Cysts
821
At the time these arches are developing, the pharynx is also actively growing. It becomes a somewhat flattened tube curved toward the front and from its lateral wall a series of four pouches protrude (Fig. 140). These internal pouches of the pharynx come in contact with the corresponding outside clefts along the most lateral aspect of the neck. Only a single cell layer may separate the pharynx from the outside at this stage as shown in Figure 141. • A glance at the embryo during these stages of development in Figures 139 and 140 is sufficient to show that all sorts of possibilities present themselves for errors of fusions of the parts that make up the face and neck and pharynx. It is, therefore, quite reasonable to assume that the
I
--Nne
(I)
Fig. 140. Relations of pharyngeal pouches to branchial clefts in a fiye weeks' embryo. The pharynx is shown schematically in heavy black outline. (T = medial thyroid anlage. L = lung bud.)
c
cysts of the neck have their origin in embryologic errors related to these growth processes. The finding of lymphoid tissue associated with squamous and other epithelium, that remind one of pharyngeal and tonsillar tissues, in so many branchial cysts is also suggestive of their origin in a junction of cleft and pouch. However, some of these cysts have no lymphoid tissue and become filled with desquamated keratin and are histologically indistinguishable from epidermal inclusion cysts. The primitive pharynx gives rise to a number of structures of interest in connection with branchial cysts, including components of the thyroid, the parathyroid glands, thymus gland, mucous glands, lymphoid (ton~ siHar) tissue, the eustachian tubes and middle ear chamber (Figs. 139 and 140). The highest or first pharyngeal pouch corresponds to and is in contact with the hyomandibular cleft (HMC) between the mandibular (M) and hyoid (H) arches; the pouch forms the eustachian apparatus
622
Samuel P. Hicks
and the cleft later corresponds to the ear and to the "line" of the lower jaw. The second pouch will correspond to the supratonsillar fossa region, and from the epithelium of the third develop the thymus and upper pair of parathyroid glands (also known as parathyroid III or parathymus). The fourth pouches are the origin of the lower pair of parathyroids
Fig. 141. Human embryo, horizontal section, 7.5 mm., about five weeks. The scant separation of pouches from clefts is evident. This would correspond to a horizontal section through the right hand member of Figure 140. (Embryo 256, Harvard Embryological Collection, courtesy Dr. George B. Wislocki, Professor of Anatomy.)
(parathyroid IV) and contribute tissue to the thyroid proper. As the lower clefts recede they form the cervical sinus which marks the future lower border of the neck. It should not be surprising, then, that branchial cysts may contain tissue whose anlagen arose from pharyngeal epithelium or other structures originating in the neck region. That the thymus should have attracted Wenglowski's attention as a prime source of neck cysts is illustrated in Figure 142 where the extended course of the thymus is
623
Branchial Cleft Cysts
shown in an embryo 19 mm. in length. Here, of course, this organ and the other pharyngeal derivatives are by now fairly well differentiated. Thymus tissue is said to occur occasionally in branchial cysts. In 100 reviewed (Table 1) for histologic characteristics in this laboratory, * no
Fig. 142. Human embryo, frontal section, 19 mm., about twenty weeks. The extent of the thymus, the thyroid and parathyroids is shown. (Embryo 828, Harvard Embryological Collection, courtesy Dr. George B. Wislocki, Professor of Anatomy.)
Table 1 HISTOLOGIC CHARACTERISTICS SEEN IN
100
Lymphoid tissue" .. " Squamous epithelium .. " . Other epithelium or closely associated glands .... " Thymus ..... " " " . " " " " " Thyroid" " . " . " " " " " " " " " " " Parathyroid. " " " " "
BRANCHIAL CYSTS
91 98 10
o
o 1
* Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts.
624
Samuel P. Hicks
unequivocal thymus tissue was seen, but one cyst did have a small parathyroid gland in its wall. In the cases reviewed, mucous glands were occasionally present in close association with the cyst. Thyroid tissue was not seen in a cyst wall, but two lesions were closely associated with the thyroid gland. There are two reasons why the presence of thyroid tissue may be a rare occurrence in branchial cysts. The first is that the pathologist would probably call such a lesion a thyroglossal cyst even if it were not quite in the midline. The other is that although the fourth pouch is incorpo-
Fig. 143. Branchial cysts. The squamous epithelium and lymphoid tissue are frequent findings, the mucous epithelium is less often seen (hematoxylin and eosin, X125). (This illustration reduced approximately 60 per cent of original photomicrograph.)
rated into the development of the thyroid, it may be .inherently less likely to be involved in errors leading to cysts. The finding of mucous glands could be attributed to an abnormal embryologic origin in some cases in which they are clearly out of place. However, in deeply or highly situated lesions the relations of these appendages might be less certain. Figure 143 shows histologic patterns that may be found in branchial cysts. It is popular to think of developmental deformities as following a rigid and predictable pattern. Actually, this is not true in medical practice. Some deformities in man and animals that are clearly due to a genetic fault-an "abnormal chromosome" in the germ cell-do follow a fairly stereotyped pattern. The developmental chemistry of the embryo is
626
Branchial Cleft Cysts
predetermined by the germ plasm, so to speak, and at a certain stage morphogenesis departs from its usual course. Other nongenetic deformities-are the result of accidents during development, that is, they are due to extrinsic forces acting on the organism during growth. Although these may mimic genetic abnormalities they are largely unpredictable, because the time and the nature of the injurious agent are not known (except in experimental embryologyB). Whether branchial cysts in man .are genetic or accidental in origin is . not known. They are classed as a disease entity, but they comprise quite a variety of patterns that must have arisen in different sites and at different periods of early embryonic development. Of what value, then, is any sort of embryologic study that tries to explain branchial cysts? There are two practical results of such studies. One is that the surgeon may anticipate that these cysts will range from relatively simple lesions to fairly complex fistulas that may involve a number of neck structures, even the pharynx. The other is that both the surgeon and the pathologist can expect to find a variety of tissues in these lesions as their embryologic origin so clearly indicates.
•
REFERENCES 1. Bailey, H.: Clinical aspects of branchial fistulae. Brit. J. Surg. 21: 173-182 (Oct.) 1933. 2. Gill, N. W.: A branchial fistula terminating in a tubulo-dermoid cyst lying posterior to the tonsil. J. Laryng. & Otol. 64: 62-69 (Feb.) 1950. 3. Hicks, S. P.: Developmental manifestations produced by radiation. Am. J. Roentgenol. 69: 272-293 (Feb.) 1953. 4. Kingsbury, B. F.: The development of the human pharynx. I. The pharyngeal derivatives. Am. J. Anat. 18: 329-397, 1915. 5. Meyer, H. W.: Congenital cysts and fistulae of the neck. Ann. Surg. 95: 1 (Jan.); 226 (Feb.) 1932. 6. Patten, B. M.: Human embryology. Philadelphia, Blakiston, 1946, 776 pp. 7. Rabl, C.: II. Zur Bildungsgeschichte des Halses. Prager med. Wchnschr. 12: 3, 1887. 8. Weller, G. L.: Development of the thyroid, parathyroid and thymus glands in man. Contributions to embryology, Carnegie Institute of Washington, No. 141, vol. 24, 1933. 9. Wenglowski, R.: ttber die Halsfisteln und Cysten. Arch. f. klin. Chir. 100: 789-892, 1913.