A rare case of malignant vagus nerve sheath tumor presenting with multiple cranial nerve dysfunction in a dog

Abstract

A 5-year-old intact male Gascon Saintongeois dog was presented with a 6-month history of coughing, laryngeal paralysis, a deglutition disorder of gradual onset, and left-sided Horner’s syndrome. The dog was admitted as an emergency for acute central vestibular signs. Magnetic resonance images identified a left extra-axial brainstem lesion extending caudally from the medulla to the vagosympathetic trunk. Histological and immunohistological examination revealed a high grade epithelioid malignant peripheral nerve sheath tumor (MPNST). This case report is the first description of a MPNST of the vagus nerve compressing the brainstem and causing multiple cranial nerve dysfunction in a dog.

Key clinical message:

Nerve sheath tumors have been reported in many locations arising from spinal nerve roots and cranial nerves. Although the trigeminal nerve is the most commonly affected nerve, other cranial nerves such as the vagus can be affected.

Peripheral nerve sheath tumors (PNSTs) arise within the nerve sheaths from 1 or more populations of endogenous cells, including Schwann cells, perineurial cells, or fibroblasts. Based on their morphologic and biologic behavior, PNSTs are divided into benign (Schwannoma, neurofibroma, perineurioma) and malignant forms (MPNSTs) (1). These tumors commonly arise from spinal nerve roots (e.g., brachial plexus, lumbosacral plexus) and cranial nerves but have also been reported in the liver, spleen, adrenal gland, skin, lungs, eyes, and other locations (2–6). The brachial plexus is the most commonly affected site in dogs (7), while trigeminal PNST is the most frequently encountered neoplasm of the cranial nerves (8,9). Reported cases of PNSTs of the vagus are rare in both human and veterinary medicine. A literature search identified only 3 reported canine cases (10–12). One dog with a malignant PNST of the right proximal cervical vagosympathetic trunk was euthanized without treatment following confirmation of cervical neoplasia (10). A second dog with a malignant vagus PNST located between the carotid artery and esophagus in the mid-cervical region had an 18-cm section of thickened vagus nerve excised during exploratory surgery. This dog was alive 19 mo after surgery at the time of the report (11). The last dog was diagnosed with an intrathoracic malignant PNST of the right vagus nerve at the level of the bronchus. A vagotomy was performed to excise a lesion measuring 2 cm in diameter and 5 cm in length, which was connected to the right vagus nerve cranially. The dog was alive 710 d after surgery at the time of the report (12). Both dogs had no signs of local recurrence or metastasis. A PNST primarily involving the hypoglossal nerve (CN XII) with secondary invasion of the vagus and accessory nerves (CN X and XI) has also been documented (13).

Peripheral nerve sheath tumors are most common in middle-aged to older dogs (8,14,15). Clinical signs depend on location of the lesion. Intracranial extension is rare but compression of the adjacent brainstem is described with trigeminal neoplasia resulting in ipsilateral proprioceptive deficits, obtundation, and/or vestibular signs (16,17). Additionally, ipsilateral clinical signs such as reduced facial and corneal sensation and face rubbing have been reported (8).

Definitive diagnosis requires histopathology, but a presumptive diagnosis can be made based on imaging findings. Magnetic resonance imaging (MRI) is the imaging modality of choice due to its superior soft tissue contrast resolution (18). Peripheral nerve sheath tumors are frequently iso- to hyper-intense on T2-weighted images, isointense on pre-contrast T1-weighted images, and display moderate to marked contrast enhancement (19).

This is the first report of a malignant vagal PNST infiltrating several other cranial nerves and causing brainstem compression. Clinical signs as well as MRI and histopathological characteristics are discussed.

Case description

A 5-year-old intact male Gascon Saintongeois dog weighing 25.1 kg was presented to the emergency department because of an acute deterioration of his neurological status, including head tilt and an inability to stand. This active hunting dog had a 6-month history of coughing. A canine infectious tracheobronchitis was first suspected by his referring veterinarian. None of the dogs of the pack had any respiratory signs. The dog was initially responsive to an oral doxycycline and prednisolone treatment lasting 2 wk, but the cough relapsed a few days after discontinuation. He was then treated with oral amoxicillin-clavulanic acid and meloxicam lasting 4 wk with partial improvement. Owing to the worsening of cough and the development of exercise intolerance, the dog was referred to our internal medicine department for investigations 4 mo before the current presentation. At that time, routine hematology and serum biochemistry were unremarkable. A test for Angiostrongylus vasorum in feces was negative. Thoracic radiographs did not show any abnormalities, while endoscopic examination of the upper respiratory tract revealed a left laryngeal paralysis and a mild tracheal collapse (grade 1). There was also evidence of chronic bronchitis with a non-specific mucosal erythema and large amounts of mucus. Cytological analysis of bronchoalveolar lavage fluid confirmed a chronic bronchitis with signs of infection in the left cranial lobe bronchus caudal segment (LB1V1) characterized by degenerating neutrophils and alveolar macrophages. Microbial testing revealed Klebsiella oxytoca that was isolated in culture, and polymerase chain reaction (PCR) testing for Mycoplasma spp. was positive. Treatment with prednisolone (CEVA Santé Animale, Libourne, France) at 1 mg/kg body weight (BW) per day in conjunction with doxycycline (Boehringer Ingelheim Animal Health, Lyon, France) at 10 mg/kg BW per day was resumed for 4 wk. Improvement was not complete, and the coughing frequency increased; in addition, ptyalism, gagging, and dysphagia developed. Prior to admission in emergency, the owner had noticed a 1-month history of left Horner’s syndrome (miotic pupil, prominent third eyelid, and droopy upper eyelid) and an abnormal gait characterized by unsteadiness for a few days.

On physical examination, the dog was dull and unresponsive, tachycardic (190 beats/min), and tachypneic (60 breaths/min). The rectal temperature was 41.8°C. The dog had semi-dry mucous membranes and a minimal loss of skin turgor. A left-sided purulent nasal discharge and left conjunctival hyperemia were also observed. On neurological examination, the dog was non-ambulatory with left-sided postural deficits along with a left-sided head tilt. There was a horizontal to rotatory nystagmus with a fast phase towards the right, an incomplete left palpebral closure, left Horner’s syndrome, and mild unilateral left temporalis muscle atrophy. Atrophy of the lingual muscles on the left side with deviation of the rostral third was also noticed. Based on the abnormal neurological findings, a neuropathy involving cranial nerves V, VII, VIII, IX, X, and XII was presumed with brainstem involvement.

Routine hematology revealed mild neutrophilic leukocytosis (14 800 cells/μL; reference range 6000 to 13 000 cells/μL) as the sole abnormal finding; serum biochemistry was unremarkable. Magnetic resonance imaging of the brain and the neck was performed with a 0.25 T scanner (Vet-MR Grande; Esaote, Genoa, Italy). Acquisition included transverse T1- and T2-weighted, dorsal FLAIR, 3D SST1, and 3D SST2 sequences. Images revealed a large, rounded, extra-axial mass with sharp margins on the ventro-lateral aspect of the brainstem at the left cerebellopontine angle, extending as a tubular lesion through the left jugular foramen and the left tympano-occipital fissure (Figure 1). The lesion appeared mildly heterogeneous on T1- and T2-weighted images with T1 hypo- and iso-intense areas and a T2 hyperintense peripheral rim with a hyper- and iso-intense center. The lesion was homogenously hyperintense on T2 FLAIR and showed mildly heterogenous and strong contrast enhancement. The mass exited the cranial vault and extended along the parapharyngeal region and formed a mass at the level of the carotid bifurcation in the area of the cranial cervical ganglion. This massive round mass (22 × 25 × 33 mm) was well-marginated, with a hypointense non-enhancing center and thick peripherally enhancing rim. Mild atrophy of the left temporal muscles was also noted. Due to the highly invasive nature of the lesion and the poor prognosis, the owner elected to have the dog euthanized and consented to a necropsy.

Figure 1.

T1-weighted transverse (a–d), dorsal (e), and parasagittal (f) magnetic resonance images obtained after IV administration of gadolinium. Transverse images (a–d) from the caudal aspect of the brainstem to C1. Note the extensive mass from the ventrolateral left side of the brainstem and along the medial aspect of the tympanic bulla. The mass is exiting at the level of the jugular foramen and tympano-occipital fissure and heterogeneously contrast enhanced, with relatively defined margins.

Gross examination at postmortem confirmed a left extra-axial brainstem mass arising from the dorsal aspect of the medulla oblongata. The elongated mass exited through the tympano-occipital fissure and emerged just caudal to the left glossopharyngeal and vagus nerves (Figure 2). The mass further encompassed the vagus and the accessory nerve and continued caudally towards the vagosympathetic trunk through the cranial cervical ganglion. The mass appeared pinkish-white, well-circumscribed, and encapsulated and did not seem to infiltrate the neighboring tissue on gross examination. Samples of normal brain tissue and of the neoplasm were fixed in 10% formalin and routinely processed for histopathological analyses.

Figure 2.

Transverse section of the formalin-fixed brain at the level of the obex. Gross findings confirmed the presence of a non-invasive tumor (arrows) causing compression of the medulla oblongata and cerebellar hemisphere.

Transverse cross sections of the lesion were stained using hematoxylin and eosin (H&E). Histologically, the mass was densely cellular with large areas of necrosis and hemorrhage (Figure 3). In some areas, neoplastic cells formed large and poorly defined sheets. These cells were round, fusiform, or stellate in shape with an abundant pale eosinophilic cytoplasm (epithelioid-like) producing a variably abundant mucinous-like matrix (Figure 4). Neoplastic cells had a large oval vesicular nucleus and a prominent nucleolus. The mitotic index was up to 4 per high power field (×400). Neoplastic cells invaded the proximal part of nerves but were not observed in the brainstem itself. Some nerve sections minimally infiltrated by neoplastic cells showed a severe loss of axons (Figure 5). This was confirmed using BIII tubulin (Promega G7121, Madison Wisconsin, USA) immunohistochemistry (IHC), a marker of neuronal cells and axons (Figure 6). In the tumor, cells were strongly positive for S100 (Abcam ab11428, Cambridge, UK), but GFAP (Dako Z0334, Santa Clara, California, USA) and BIII tubulin negative. Immunohistochemical staining was performed using standard avidin-biotin-peroxidase complex (ABC) method. Based on the macroscopic, microscopic, and IHC evaluations, the morphological diagnosis of a high grade, poorly differentiated, epithelioid, malignant vagus peripheral nerve sheath tumor was reached. Two lymph node segments obtained proximal to the tumor did not show any evidence of metastasis.

Figure 3.

Histopathology (H&E stain, tumor). At low magnification significative amount of necrosis (stars) admixed with hemorrhages (arrow) are observed (×20).

Figure 4.

Histopathology (H&E stain, tumor). Neoplastic cells (arrows) are poorly differentiated, round to fusiform and arranged in poorly demarcated large sheets with variable amount of extracellular myxoid material (×1000).

Figure 5.

Histopathology (H&E stain, nerve section). Abnormal nerve section shows low number of infiltrating neoplastic cells (cells with larger nuclei) (arrows). Note the absence of axons in the nerve (Schwann cells only) (arrowheads) (×1000).

Figure 6.

Immunohistochemistry (nerve section). BIII tubulin IHC revealed the almost complete absence of axons in several nerve sections; only small remaining fragments of axons (arrows) were observed (×1000).

Discussion

Clinical and pathological examinations in this case revealed a tumor derived from the left vagosympathetic trunk. This case is unique because of the unusual presentation of clinical signs, the highly expansive nature of the tumor, and the resulting compression causing multiple cranial nerve dysfunction.

The vagus nerve provides both sensory and motor innervation to the palate, pharynx, larynx, trachea, and esophagus, as well as to thoracic and abdominal organs (20). The efferent axons in the vagus arise from 2 nuclei located in the medulla oblongata. The somatic efferent fibers have their cell bodies in the nucleus ambiguus from which the glossopharyngeal nerve (IX) arises rostrally and the cranial root of the accessory nerve (XI) arises caudally. These nerves emerge very close to each other, lateral to the myelencephalon, exit the jugular foramen and tympano-occipital fissure, and course down to supply the musculature of the pharynx, larynx, and esophagus. These nerves cannot be differentiated from each other on MRI (21).

The dog was initially presented for coughing, inspiratory dyspnea, and exercise intolerance. A chronic bronchitis was diagnosed associated with a unilateral left laryngeal hemiplegia. The cause of the chronic bronchitis was unclear but thought likely to reflect a swallowing disorder and laryngeal tracheal mucosal irritation. All laryngeal muscles, except for the cricothyroideus, are innervated by the recurrent laryngeal nerve, which branches from the vagus nerve at the level of the heart base (on the left) or rostral to the heart base (on the right) (20). Therefore, a lesion in the cervical vagosympathetic trunk can be expected to induce ipsilateral laryngeal hemiplegia, which could predispose the affected patient to aspiration. Radiographic evidence of aspiration pneumonia was not apparent initially, although recheck radiographs were not performed.

Laryngeal paralysis is usually diagnosed by examination of the movement of arytenoid cartilages and vocal cords, either via direct visualization when the patient is conscious or using ultrasonography or computed tomography (CT) (22). In equivocal cases, electromyography is helpful. Polyneuropathy complex and idiopathic laryngeal paralysis are the most frequent causes of laryngeal paralysis, but other diseases must be considered, such as accidental or iatrogenic trauma to the recurrent laryngeal nerve, toxicity (lead or organophosphates), primary neoplasia, or secondary to processes such as thyroid masses or brainstem inflammatory or neoplastic diseases (22).

Over time, dysphagia became obvious in this patient. Swallowing disorders can occur with mechanical (anatomical), functional (neurological), or pain-related disorders. Functional dysphagia can occur with lesions in the nucleus ambiguus of the medulla, the glossopharyngeal (IX) and vagus (X) nerves, or the pharyngeal or esophageal muscles. In this case, the dysphagia was secondary to a primary dysfunction of cranial nerves IX and X. Furthermore, the characteristic combination of a miotic pupil, prolapsed third eyelid, and upper eyelid ptosis indicating Horner’s syndrome was observed by the owner. Symptoms related to Horner’s syndrome result from dysfunction of the sympathetic supply along its 3-neuron pathway. For this dog, a second neuron lesion in the cranial cervical vagosympathetic trunk most likely resulted in Horner’s syndrome due to disruption of the sympathetic supply to the ipsilateral eye.

Considering the evolution of the clinical signs and the results of the initial diagnostic tests, a neoplastic disorder was the main hypothesis. In light of MRI sequences, anatomopathological, and histological findings, a tumor originating from the left vagosympathetic trunk was presumed. Over the course of a couple months, the tumor likely gradually infiltrated other cranial nerves such as glossopharyngeal and accessory nerves, and compressed the brainstem causing the more recently central nervous signs observed (central vestibular syndrome, proprioceptive deficits, and obtundation). A mild left temporal muscle atrophy observed on MRI was presumed to be secondary to involvement of the mandibular branch of the trigeminal nerve.

Intracranial PNSTs are relatively uncommon tumors in dogs. The most common cranial nerve involved is the trigeminal nerve (8,14,19). Case reports describing other cranial nerve sheath tumors are rare (10,11,13). Various diagnostic imaging modalities have been reported in the diagnosis of PNSTs (8). Computed tomography and MRI are both appropriate options for identifying affected nerves, nerve root involvement, and potential vertebral canal or intracranial extension. In this case, MRI was chosen as it provides excellent soft-tissue resolution and has the ability to distinguish nerve bundles from vessels (8,18,19).

Histopathology findings confirmed the diagnosis of a high-grade epithelioid malignant PNST in this dog. Malignant PNSTs are derived from Schwann cells or pluripotent cells of the neural crest and can be graded according to the WHO classification. Several distinct subtypes have been recognized including “Schwannoma,” “Neurofibrosarcoma,” or “Neurosarcoma.” A malignant poorly differentiated PNST is usually defined as a tumor with nerve sheath differentiation and neoplastic cell invasion beyond the confines of the epineurium. Grossly, these tumors lack an epineural tumor capsule and may aggressively invade the surrounding structures. At microscopic examination, PNSTs are generally characterized by spindle-shaped cells arranged in palisades or spiral shapes (Antoni A & B patterns or Verocay bodies) (23). In our case, these specific patterns, more frequently observed in low-grade tumors, were not observed. The epithelioid nature of this malignant PNST was based on the presence of neoplastic cells with an abundant eosinophilic cytoplasm and the presence of a myxoid matrix frequently described in tumors of this type in literature on humans cases (WHO classification) (24). Malignant PNSTs are frequently S100 positive and variably positive for GFAP (1). BIII tubulin is a neuronal marker which allowed us to visualize the marked loss of axons in several nerve sections present on tissue sections. This observation was consistent with the multiple cranial nerve dysfunctions observed in this case.

Treatment of malignant PNSTs involves the removal of the tumor when surgically accessible, radiation therapy, or both (14,25,26). Without treatment, survival times for dogs with trigeminal PNST range from 5 to 21 mo and affected dogs typically die as a result of tumor invasion of the adjacent brainstem structures (8). The prognosis for PNSTs is variable and mainly dependent on the treatment. Local recurrence is common, with a guarded to poor long-term prognosis.

Tumor removal was not considered in this case due to the highly expansive nature of the tumor and the intracranial involvement. Indeed, intracranial nerve surgeries are rarely performed due to the combination of a challenging approach and a high postoperative morbidity rate (8). If the lesion had been confined to the cervical region, a surgical excision might have been proposed. Two case reports described successful vagotomies with tumors located in the mid-cervical region and intrathoracic location allowing resolution of the clinical signs induced by vagal dysfunction (11,12).

Radiation therapy is currently the preferred treatment modality for most patients with trigeminal PNSTs. One retrospective analysis demonstrated that stereotactic radiotherapy (SRT) is a beneficial and well-tolerated treatment option (25). In this study, 8 dogs treated by stereotactic radiotherapy [3 doses of 8 Gray (Gy)] had a mean disease-specific survival time of 745 d (range: 99 to 1375 d). In another study (14) including 15 dogs treated by SRT with 3 fractions of 8 to 10 Gy megavoltage radiation, the median survival time was 441 d. Curative intent high dose hypofractionated frameless volumetric modulated arc radiotherapy for treatment of trigeminal PNST has also been evaluated (27). Overall, median survival was 952 d with a 95% confidence interval of 543 to 1361 d. When considering spinal PNSTs, it has been described that dogs treated with SRT as a second-line treatment after tumor recurrence, following surgery alone or having already solely received SRT as their initial treatment, may gain an additional 125 to 346 d survival time (26).

Chemotherapy is not commonly used alone or in conjunction with surgery or radiation for peripheral nerve sheath tumors. Palliative care includes corticosteroids to reduce cerebral edema if present.

This case report describes an uncommon presentation of a malignant PNST in a dog. Clinical signs progressed over 6 mo, presenting initially as coughing with a suspicion of unspecific bronchitis and laryngeal hemiplegia progressing with dysphagia and Horner’s syndrome eventually resulting in a multifocal brainstem dysfunction. We strongly recommend functional laryngeal assessment for cases with no apparent radiographic causes for chronic cough and no improvement with empiric drug therapy. In addition, should laryngeal dysfunction be observed, advanced imaging investigations such as MRI should be considered to assess structures related to vagal innervation. CVJ