Pharyngeal Pouch and Cleft Remnants in the Dog and Cat: A Case Series and Review
Remnants of the pharyngeal apparatus can (rarely) form cysts. This retrospective case series describes clinical and histologic findings of such lesions. Clinical and histology databases were searched for cases of pharyngeal remnants. Eight patients were diagnosed with cysts located subcutaneously in the head and neck, adjacent to the submandibular salivary gland, near the thyroid, and in the mediastinum. Cyst linings included ciliated epithelium, and surgical excision was curative. Knowledge of pharyngeal development is useful for their characterization. Clinicians should consider pharyngeal remnants as differentials for cystic lesions in small animals.
Introduction
Pharyngeal cysts, sinuses, and fistulae are the result of anomalous regression of the pharyngeal pouches or pharyngeal clefts. The pharyngeal pouches are a series of four to five bilateral evaginations of the pharyngeal endoderm that project laterally between the pharyngeal arches (Figures 1A, B).1,2 They are apposed by ectodermally derived pharyngeal clefts (also called pharyngeal or visceral grooves) that externally divide the pharyngeal arches (Figure 2).1–3 The pharyngeal pouches and clefts contribute to the formation of a number of adult structures, including the thymus, parathyroid gland, pharyngeal tonsils, and middle and external ear.3 The term “branchial” has been commonly used to refer to these structures and their remnants in human and veterinary species, but “pharyngeal” is preferred, as the formation of these structures does not lead to the formation of true gills (branchia) in mammals as it does in fish and amphibians.3
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5728
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5728
Cystic lesions associated with pharyngeal remnants of the submandibular region and neck have been sporadically reported in canine and feline patients. These cysts are histologically differentiated from similar lesions by the presence of pseudostratified columnar or focally squamous, partially ciliated, epithelium that derives from the embryonic pharynx.4 Excluding those reports that lack histologic assessment of the cyst lining, only a small number of pharyngeal cysts involving the head and neck have been reported in veterinary patients (Table 1).5–12
Pharyngeal remnants in the thymus or mediastinum have also been described. Multiple small to microscopic thymic cysts lined by pseudostratified ciliated to squamous epithelium have been described as incidental findings in older dogs.13–15 Liu et al. (1983) described thymic cysts in 15 dogs and 2 cats. In some cases an inflammatory response to the cystic lesions and significant associated disease were noted.16 Pleural effusion was noted in all cases, and 3/15 dogs exhibited cranial vena cava syndrome. It remains uncertain whether these epithelial cysts of the thymus arise from anomalous remnants of the third pharyngeal pouch or from thymic epithelium, particularly because cystic changes are rarely present in young dogs.14,15
In this report, the clinical, diagnostic, and histologic findings associated with a series of six dogs and two cats diagnosed with remnants of the pharyngeal pouches or clefts based on histologic findings from surgical biopsy samples are described. The formation of the pharyngeal apparatus in the mammalian embryo is reviewed and the authors conjecture on the likely origins of its remnants in small animal patients.
Materials and Methods
The medical records database of Michigan State University Veterinary Teaching Hospital was searched for diagnoses including “branchial,” “lateral neck cyst,” “pharyngeal pouch cyst,” “cervical cyst,” and “mediastinal cyst.” The medical records of all hospital patients were retrieved and details of their clinical history, treatment, and diagnostic testing recorded. Owners and referring veterinarians were contacted for follow-up.
In addition, the histology database of Michigan State University Diagnostic Center for Population and Animal Health was searched for biopsy specimens characterized as branchial or pharyngeal in origin. For cases identified through biopsy specimens submitted to the diagnostic laboratory by other clinics, the attending veterinarian was contacted and clinical history and follow-up information obtained.
Results
From 224,454 canine and feline patients presented to the hospital over a 14 yr period (1994–2008), three cases (all dogs) were identified. Five additional cases, including three dogs and two cats, were identified from 134,895 biopsy specimens analyzed by the diagnostic laboratory over the same period. Case details have been summarized in Table 2.
Case Report
Case 1
A 4 yr old castrated male Labrador retriever mixed-breed dog was evaluated for a firm mass in the right submandibular region. The mass was initially noted by the owner 18 mo before presentation and was initially the size of a golf ball. The mass enlarged over a period of months to approximately twice its initial size.
Physical examination revealed an approximately 8 cm firm, smooth, fixed, nonpainful mass palpable caudal to the right mandible and indistinguishable from the mandibular salivary gland. Fine-needle aspiration (FNA) of the mass yielded several mL of thin, opaque, flocculent brown fluid. After centrifugation, the fluid was yellow and hazy. Specific gravity was 1.035, total protein was 6.0 g/dL, with an estimated 10,000 cells/μL (manual count) and a packed cell volume <2%. Cytology demonstrated minimal blood and large amounts of proteinacious material containing vague, small, amorphous basophilic and eosinophilic areas. Nucleated cells consisted of low numbers of neutrophils and macrophages, the latter of which often contained moderate to large amounts of nonstaining to eosinophilic granular debris. Moderate amounts of hematoidin were present both within macrophages and extracellularly. Atypical cell populations were not noted.
Ultrasonography of the neck demonstrated a 3.3 cm × 5.6 cm × 7.2 cm rounded to tubular, thin-walled, fluid-filled structure. This structure originated from the right mandibular salivary gland and extended medial, cranial, and dorsal (Figure 3). The entire length of the structure could not be seen due to its extension medial to the petrous temporal bone near the ear base. The majority of the salivary gland parenchyma was replaced by this structure, with the visible portion of the gland within normal limits.
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5728
Based on the association of the cyst with the salivary gland, surgical removal of the right mandibular salivary gland, duct, and the associated monostomatic sublingual salivary gland and duct were performed through a ventral approach.17 Grossly, the cyst was continuous with the capsule of the right mandibular salivary gland and extended cranially and dorsally from the gland in the direction of the salivary duct. The cyst was bluntly dissected away from deeper structures, removed en bloc with the associated mandibular and sublingual salivary glands, and submitted for biopsy. Histopathologic findings have been summarized in Table 2 and depicted in Figures 4A, B. No recurrence was noted at the last follow-up 8 mo postoperatively.
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5728
Case 2
A 10 yr old spayed female keeshond presented for treatment of primary hyperparathyroidism diagnosed based on elevated parathyroid hormone (107.00 pmol/L; reference range, 3.00–17.00 pmol/L) and ionized hypercalcemia (2.25 mmol/L; reference range, 1.35–1.45 mmol/L). The dog was also azotemic based on a biochemical profile performed prior to referral.
On presentation, no abnormalities were noted on physical examination. Urinalysis showed isosthenuria (urine specific gravity was 1.016) with active sediment (>60 erythrocytes and leukocytes/high-power field and many rod-shaped bacteria). Urine culture confirmed the presence of Escherichia coli. A complete blood cell count (CBC) was unremarkable. Abdominal ultrasonography showed bilateral renal mineralization and multiple cystic calculi. Thoracic radiographs were unremarkable.
Surgery was performed to remove a presumed parathyroid adenoma and cystic calculi. A nodule, confirmed histologically as a parathyroid adenoma, was removed with the caudal pole of the right thyroid gland. A cystic mass was noted at the caudal pole of the left thyroid gland and was excised with the caudal pole of the left thyroid gland and submitted for histopathology (Table 2). Postoperatively, the dog was treated with oral calcitriola (1 ng per os [PO] q 24 hr), calcium carbonateb (0.5 g PO q 12 hr), and cephalexinc (22 mg/kg PO q 12 hr). Serial venous blood gas analysis demonstrated a characteristic progressive normalization of ionized calcium values over the 4 days following removal of the parathyroid adenoma. The patient was euthanized for continued elevation in renal parameters 3 yr after surgery, with no noted recurrence of hypercalcemia or cystic masses.
Case 3
A 10 yr old castrated male mixed-breed dog presented for evaluation of a 10 day history of vomiting and diarrhea, which resolved with supportive fluids administered by the referring veterinarian during the course of hospitalization. At presentation, an abdominal mass was suspected based on radiography. Three-view thoracic radiographs were performed to assess for metastatic disease, which showed a large cranial mediastinal mass. On ultrasonography, this mass was well-defined with mildly heterogenous echogenicity and focal areas suspected to represent necrosis. The ultrasonographic findings in the abdomen were suggestive of gastroenteritis and splenomegaly with coarse echotexture. Splenic cytology was unremarkable. Cytology of the mediastinal mass showed chronic hemorrhage and occasional spindle cells. No clinically significant abnormalities were noted on biochemical profile, CBC, or urinalysis apart from mildly increased liver enzyme activity. Further characterization of the mediastinal mass was achieved with computed tomography, which showed no evidence of vascular invasion. The mass was removed through a median sternotomy.
At surgery, an approximately 10 cm diameter, well-circumscribed, brown, lobulated mass was identified in the cranial mediastinum. The mass was bluntly dissected away from underlying structures with gentle pressure. The internal thoracic arteries and veins were ligated and transected bilaterally to allow removal of the mass, which was then submitted for histopathology (Table 2).
The patient recovered uneventfully. Six weeks postoperatively, marked bilateral prescapular lymphadenopathy and moderate popliteal and axillary lymphadenopathy were noted. Cytology and immunohistochemistry of the left prescapular lymph node were consistent with B cell lymphosarcoma. Ionized hypercalcemia was noted on a venous blood gas analysis (6.0 mg/dL; reference range, 3.4–5.3 mg/dL). The dog's owners declined further staging. After an initial response to dexamethasone SPd, diphenhydraminee, and L-asparaginasef, recurrent lymphadenopathy was noted and further treatment was declined.
Case 4
An 8 yr old castrated male Shetland sheepdog presented to his primary veterinarian for removal of two nonpainful, cystic, subcutaneous masses on the ventral neck. The masses were initially noted 18 mo previously. FNA of the masses at the time of initial diagnosis yielded clear fluid. By the time of surgery, the left-sided mass had increased from 2 cm to 6–7 cm in diameter. The mass on the right side was more oblong and had decreased from 3 cm to 2 cm in diameter. The masses were located superficially in the subcutaneous tissue, were removed en bloc, and submitted for histopathology (Table 2). Eighteen months after surgery, there was no evidence of cyst recurrence.
Case 5
A 9 yr old spayed female standard poodle presented to her primary veterinarian for removal of a cystic subcutaneous mass on the right lateral neck ventral to the ear. The mass was first noted 11 mo previously at which time 4 mL of acellular fluid was removed by FNA. At the time of presentation, the 2–3 cm diameter mass was removed under general anesthesia. Gross sectioning of this mass demonstrated a fluid-filled, thin-walled cyst, which was submitted for histopathologic evaluation (Table 2). No recurrence of the cyst was noted 8 mo postoperatively.
Case 6
A castrated male whippet presented to a referral hospital for evaluation of an incompletely excised grade 2 mast cell tumor on the left shoulder. The scar of the previous mass excision was re-excised, and a small subcutaneous mass was also removed from the ventral aspect of the mandible. All excised tissue was submitted for histopathology. The excised scar did not show evidence of neoplastic cells. The subcutaneous mass near the mandible was determined to be a cyst (Table 2). Further follow-up was unavailable for this case.
Case 7
An 8 yr old female domestic shorthair presented to her primary regular veterinarian for evaluation of a fluid-filled mass in the area of the right thyroid gland. The mass was removed and submitted for histopathology (Table 2). No further clinical follow-up was available for this case.
Case 8
A 4 yr old castrated male domestic shorthair presented to his primary veterinarian for removal of a moveable 0.7 cm mass in the subcutaneous tissue of the ventral neck that had been present for several months. The mass was removed and submitted for histopathologic analysis (Table 2). Five years after surgery, no evidence of mass recurrence was noted.
Discussion
During embryonic development, the pharynx is surrounded laterally and ventrally by mesenchyme of neural crest origin that forms the skeletal and connective tissues of the pharyngeal arches. The first four pairs and sixth pair of pharyngeal arches (numbered rostral to caudal) contribute to the structural, neural, and muscular formation of the face, inner ear, nasal cavities, mouth, larynx, pharynx, and neck. The fifth arch is rudimentary and leaves no derivatives in the adult.3
Pharyngeal clefts (also numbered rostral to caudal) develop in the ectoderm between each pharyngeal arch. The first pharyngeal cleft contributes to the formation of the external ear as the external acoustic meatus. The second pharyngeal arch enlarges and overgrows the third and fourth arches, forming an ectodermal depression called the cervical sinus, which encompasses the other clefts (Figures 5A–D).2 These clefts and the cervical sinus are normally obliterated during continued development of the neck.1
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5728
The pharyngeal pouches are a series of four to five pairs of lateral evaginations of the pharyngeal endoderm between the pharyngeal arches. The lateral aspect of each pouch extends dorsally and ventrally and apposes the associated ectodermal pharyngeal cleft to create pharyngeal membranes. The first pharyngeal membrane persists as the tympanic membrane in the adult. The endodermal epithelium of the pharyngeal pouches gives rise to a number of important structures in the head and neck (Figure 5).2 The fate of each pharyngeal pouch is summarized in Table 3. All but the dorsal aspect of the first pharyngeal pouch and the second pharyngeal pouch lose their connections to the pharynx.3
The follicular epithelium of the thyroid gland is not of pharyngeal pouch origin. Instead, the follicular epithelium arises from an endodermal epithelial proliferation in the floor of the pharynx (the foramen cecum). The thyroid tissue descends ventral to the pharyngeal gut, initially remaining connected to the tongue by a narrow canal called the thyroglossal duct, which later disappears (Figure 5).2 The thyroid gland descends ventral to the hyoid apparatus and larynx before coming to rest along the trachea.1 Thyroglossal duct cysts are remnants of the descent of the thyroid primordium from the pharynx near the base of the tongue to its adult position in the neck. Such cysts occur directly on midline or just paramedian, with 80% of such cysts located at or below the level of the hyoid bone. In contrast to pharyngeal cysts, thyroglossal duct cysts are lined by multilayered thyroidogenic epithelium.4 Thyroglossal duct cysts have been reported in the cat.18,19
Due to the location and diversity of structures that arise from the pharyngeal clefts and pouches, malformations of the developing pharyngeal apparatus can manifest in a variety of ways. Congenital cervical sinuses, cysts, and fistulae arising from the head and neck have been reported in both the veterinary and human literature.4,20 In addition, non-neoplastic cystic changes associated with the thyroid glands, parathyroid glands, and thymus may be due to remnants of the third and fourth pharyngeal pouches. Cysts are defined as epithelium-lined malformations with no external opening. Sinuses are malformations with one superficial opening, and fistulae are defined as malformations with both internal and external openings.21
Pharyngeal cleft and pouch malformations are diagnosed based on their location and presumed origin. Malformations of the first cleft are rare in humans and are classified into two types. Type I lesions are ectodermal duplications of the external auditory canal that course lateral to the facial nerve and present as swellings near the ear, but may also be either in the parotid gland or at the angle of the mandible.20,21 Type II lesions have ectodermal and mesodermal components (such as cartilage), pass medial to the facial nerve, and present as preauricular, infra-auricular, and postauricular swellings associated with the submandibular gland. Alternatively, type II lesions are found in the anterior triangle of the neck.20,21
Lesions associated with the second pharyngeal cleft and pouch are the most common pharyngeal remnant malformations in humans, representing 95% of all such malformations.21 These “lateral neck cysts” are often attributed to failure of the second pharyngeal cleft and cervical sinus to regress.3 However, it is difficult to differentiate ectodermally derived nasal respiratory epithelium and endodermally derived bronchial and pharyngeal respiratory epithelium based on morphologic appearance.22 Regauer et al. (1997) examined 97 cases of lateral neck cysts and, based on the lack of cytokeratin 14 expression in endodermally derived ciliated respiratory cells, classified them as being of second pharyngeal pouch origin.22 This theory is supported by the occasional communication of these abnormalities with the supratonsillar fossa.20,23 These cervical lesions most commonly present as a fistula or cyst in the lower anterolateral neck, with cysts more common in adults and fistulae in either infancy or childhood.20 Lateral neck cysts are subclassified by location, with type I cysts superficial to the anterior border of the sternocleidomastoid muscle, type II cysts lateral to the carotid sheath and posterior to the submandibular gland, type III cysts passing between the internal and external carotid arteries to the lateral wall of the pharynx, and type IV cysts located deep to the carotid sheath abutting the pharynx.20,24 Type II cysts are the most common.24
In the current study, half of the lesions (cases 4, 5, 6, and 8) occurred in the subcutaneous tissues of the head and cranial neck. Although precise locations of the lesions on each patient are not available, these lesions are most likely remnants of the first pharyngeal cleft or second pharyngeal pouch. Only one of these lesions appeared to be a sinus (case 8), with most lesions being clinically and histologically consistent with cysts. Based on its location ventrolateral to the mandibular salivary gland and deeper location, the cyst removed from case 1 is most consistent with a type II remnant of the second pharyngeal pouch.
Cystic malformations associated with anomalous development of the third and fourth pharyngeal pouches have been described, but are rare in humans.21,24 Thymic pharyngeal pouch cysts (third pharyngeal pouch) have been described as pathologic findings in the dog and cat.16 Thymic cysts are more common in older dogs and may be due to cystic proliferation of thymic reticular cells rather than embryonic rudiments of the pharyngeal apparatus.15 Thymic cysts have been described in 59% of beagles 28–30 mo of age in one study, suggesting that they can be incidental findings.14 In cats, only two reports of pharyngeal pouch malformations in the lower cervical region are available: one of a 5 mo old kitten with a pharyngeal sinus and cyst extending from the pharynx caudal to the thoracic inlet, and one of a 13 yr old cat with a cyst extending along the dorsolateral aspect of the trachea to the level of the thoracic inlet.11,12 Parathyroid or thymic involvement were not specifically noted in either case, although a remnant of the third or fourth pharyngeal pouch is most likely.
In this report, one cyst was associated with the caudal aspect of the thyroid gland (case 2), which is consistent with a remnant of the ventral aspect of the fourth pharyngeal pouch. The cyst in case 7 may have derived from the third or fourth pharyngeal pouch as the relationship of this lesion to the thyroid and parathyroid glands is unknown. Finally, the thymic lesion in case 3 is most consistent with a remnant of the ventral portion of the third pharyngeal pouch.
The epithelial lining of pharyngeal cleft and pouch cysts can vary from squamous to ciliated respiratory epithelium. Some reports use the type of epithelium as a determinant of the tissue of origin, with pseudostratified columnar epithelium associated with endodermal pharyngeal pouch remnants and squamous epithelium associated with ectodermal pharyngeal cleft remnants.9 Subsequent reports suggest that malformations of the pharyngeal cleft or pouch origin are lined initially by ciliated columnar respiratory epithelium that is gradually replaced by ciliated pseudostratified epithelium, followed by nonciliated transitional pseudostratified epithelium, and eventually, squamous epithelium.22 Previously reported pharyngeal remnant cysts in dogs and cats have featured nonciliated, pseudostratified, columnar, simple columnar, cuboidal, squamous, and stratified squamous epithelium, occasionally with more than one epithelial type present.7,8,11,12 In the current case series, cilia were present in all samples, with epithelial types including simple columnar, squamous, cuboidal, and pseudostratified columnar. Multiple epithelial types were present in all but one case (case 5).
All patients identified in this series were adult at the time of diagnosis, which is consistent with human reports.20,21,24 The definitive diagnosis of pharyngeal remnant was made based on histopathology in all cases. Histopathology is necessary to differentiate pharyngeal pouch/cleft cysts from other cystic neoplastic and non-neoplastic lesions.25 Because of the rarity of pharyngeal remnants in comparison with other cystic masses of the head and neck, appropriate preoperative diagnostics including cytology, thyroid and parathyroid hormone levels, biochemical profile, CBC, focal imaging, and staging for evidence of metastatic disease should be considered prior to surgery. Ultrasonography of the neck was valuable in characterizing the type of mass present in case 1 and to determine its origin. The lesions were identified by palpation in six of eight cases described in this report. In two cases, pharyngeal cysts were incidental findings identified during diagnostic testing (case 3) and parathyroidectomy (case 2). Complete surgical excision was accomplished in the majority of cases in this study. No evidence of local recurrence was documented in cases for which follow-up was available.
Conclusion
Cysts of pharyngeal cleft or pouch origin are uncommonly diagnosed in the head, neck, and thorax of small animal patients. An understanding of the embryologic development of the pharyngeal apparatus provides an important understanding of the potential extent and origin of cysts, fistulae, or sinuses diagnosed in these areas. Complete surgical excision of pharyngeal cleft and pouch remnants is likely curative.
A: Lateral view of an embryo indicating the plane of section for Figure 1B. B: Pharyngeal arches (I-VI) are shown with artery, vein, and cartilage. The endodermally derived pharyngeal pouches (1–4) are shown along the developing pharynx. This figure was adapted with permission from Essentials of Domestic Animal Embryology. Sinowatz F, Vejlsted M. Page 227. Copyright Saunders/Elsevier 2010.2
Horizontal section of a developing human embryo at 5 wk showing the pharyngeal arches, pouches, and clefts. Note that the second pharyngeal arch grows over the third and fourth arches, burying the second to fourth pharyngeal clefts. This figure was adapted with permission from The Developing Human: Clinically Oriented Embryology, 8th Ed.. Moore KL, Persaud TVN, Torchia MG. Page 168. Copyright Saunders/Elsevier, 2008.3
Parasagittal ultrasonographic image of the right mandibular salivary gland (RT MAND SAL) of case 1. A large cystic structure replaces most of the salivary gland's parenchyma. A rim of remaining normal salivary parenchyma is seen on the right of the image (arrows).
A: 100× photomicrograph of the wall and epithelial lining of the second pharyngeal pouch cyst removed from case 1. B: 200× photomicrograph of the epithelial lining of the same lesion, demonstrating areas of squamous (*) and ciliated pseudostratified columnar epithelium (†). Hematoxylin and eosin staining.
Development of the pharyngeal arches, pouches, and clefts. A: The pharyngeal pouches (1–4), first and second pharyngeal arches (I and II), thyroid primordium (7), and thyroglossal duct (7′) are shown. A caudal extension (6) of the second pharyngeal arch is shown overgrowing the second to fourth pharyngeal clefts, creating the cervical sinus (5). B–D: The pharyngeal pouches differentiate, and the following structures are noted: palatine tonsil (2), primordium of thymus (8), primordium of external parathyroid gland (9), primordium of internal parathyroid gland (9’), and ultimobranchial body (10). This figure was adapted with permission from Essentials of Domestic Animal Embryology.: Sinowatz F, Vejlsted M. Page 227. Copyright Saunders/Elsevier 2010.2
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