Malignant peripheral nerve sheath tumor in the vagus nerve causing upper gastrointestinal signs in a dog

Abstract

Peripheral nerve sheath tumors (PNSTs) originating from the vagus nerve are rare in dogs. This paper reports a canine case of malignant PNST originating from the vagus nerve, specifically the vagus-sympathetic trunk, which induced notable gagging and chronic vomiting. The clinical signs improved after surgery despite incomplete resection, and the dog achieved an overall survival of at least 514 days. These observations suggest that surgical intervention may be beneficial in dogs with malignant PNSTs originating from the vagus nerve.

Peripheral nerve sheath tumors (PNSTs) originate from Schwann cells, perineural cells, or fibroblasts [6] and are histologically classified as benign or malignant. In dogs, PNSTs originating from the vagus nerve are rare, and to our knowledge, only four cases have been reported [2, 4, 9, 11]. The clinical signs varied among the cases and included coughing, laryngeal paralysis, vomiting, gagging, Horner’s syndrome and multiple cranial nerve dysfunctions due to medullary compression. There is no established therapeutic strategy, and euthanasia was proposed in some previously reported cases [2, 9]. However, there have also been reports of cases successfully treated with surgery [4, 11]. As the clinical features of PNSTs originating from the vagus nerve remain unclear, it is essential to accumulate knowledge about cases with similar conditions.

This paper reports a canine case in which a malignant PNST originating from the vagus-sympathetic trunk caused notable gagging and vomiting. The clinical signs significantly improved after surgical treatment, although resection was incomplete, and an overall survival of at least 514 days was achieved.

A 12-years-old intact male Shiba dog weighing 8.8 kg presented to the Veterinary Medical Center of the University of Tokyo with a two-month history of frequent vomiting, decreased appetite, and weight loss (Day 1). While the chief concern of the owner was the vomiting, the video provided by the owner recorded independent post-vomiting gagging (Supplementary Video 1). This gagging was observed several dozen times a day. Physical examination, complete blood count, serum biochemistry, thoracic X-ray and abdominal ultrasound revealed no abnormalities.

Computed tomography (CT) revealed a mass lesion measuring 13 mm (left-to-right) × 12 mm (dorsoventral) × 20 mm (head-to-tail) on the left side of the larynx (Fig. 1A, 1B). The vagus-sympathetic trunk ran close to the ventral side of the mass with adhesion or continuity to the mass (Fig. 1B). The mass was also adjacent to the medial retropharyngeal lymph node but not to the thyroid gland, and there was no evidence of compression of the pharyngeal region by the mass (Fig. 1C). No metastatic lesion was observed. Subsequent cervical ultrasonography revealed a hypoechoic mass lesion, approximately 14 mm in size, in the left cervical region, with the continuity observed with a round structure that appeared to be a slightly enlarged vagus-sympathetic trunk (Fig. 2). Cytological examination revealed a mildly hemorrhagic, proteinaceous background containing a moderate number of individual and clustered stromal cells (Fig. 3). These fusiform to slightly oval cells were occasionally accompanied by a small amount of eosinophilic extracellular matrix and showed predominantly naked nuclei.

Fig. 1.

Computed tomography (CT) findings on Day 1. (A) Axial section: a well-circumscribed mass lesion (blue arrowheads) measuring 13 mm (left-to-right) × 12 mm (dorsoventral) was observed on the left side of the larynx. The mass was solid and showed a heterogeneous and mild contrast enhancement. (B) Sagittal section: the mass (blue arrowheads) measured 20 mm from head to tail. The vago-sympathetic trunk (yellow arrowhead) was observed to run close to the ventral side of the mass, raising the suspicion of adjacent or continuity with the mass. The left common carotid artery (red arrowheads) was observed adjacent to the ventral side of the mass. (C) Coronal section: the mass (blue arrowheads) was adjacent to the medial retropharyngeal lymph node (green arrowheads). There was no evidence of compression of the pharyngeal region by the mass.

Fig. 2.

Cervical ultrasonography findings on Day 1. A hypoechoic mass lesion (as indicated by the white asterisk) of approximately 14 mm in size was observed in the left cervical region, showing continuity with a round structure that appeared to be a slightly enlarged vagus-sympathetic trunk (as indicated by white star). The left common carotid artery appeared blue on color doppler imaging.

Fig. 3.

Cytological examination. A mildly hemorrhagic, proteinaceous background contained a moderate number of individual and clustered stromal cells. These fusiform to slightly oval cells showed predominantly naked nuclei and were occasionally accompanied by a small amount of eosinophilic extracellular matrix (600×). Bar=20 µm.

At surgery performed on Day 18, a mass involving the vagus-sympathetic trunk was identified (Fig. 4A, 4B), and the mass and the adjacent medial retropharyngeal lymph node were surgically resected. Sections were prepared from formalin-fixed paraffin-embedded specimens and stained with hematoxylin and eosin. Histologically, a tumor with an undefined margin was observed in the vagus nerve (Fig. 5A). The tumor was composed of spindle to polygonal cells arranged in bundles (Fig. 5B). The tumor cells had ovoid, euchromatic nuclei showing moderate anisokaryosis and a scant eosinophilic cytoplasm (Fig. 5C). Mitotic count was 9 per 10 high-power fileds (2.37 mm²). The tumor infiltrated the vagus nerve tissue and tumor cells were observed at the resection margin. Based on these findings, the tumor was histopathologically diagnosed as a malignant PNST of the vagus nerve and was considered incompletely resected. No metastatic lesion was observed in the medial retropharyngeal lymph node.

Fig. 4.

(A) The mass observed during the surgery on Day 18. The mass involved the vagus-sympathetic trunk (the head of the patient is on the left). (B) The resected mass measured approximately 5 cm.

Fig. 5.

Histopathological findings of the mass lesion. Hematoxylin and eosin staining. (A) A tumor with undefined margin in the vagus nerve. Bar=5 mm. (B) The tumor is composed of spindle to polygonal cells arranged in bundles. Bar=100 µm. (C) The tumor cells have ovoid, euchromatic nuclei showing moderate anisokaryosis and a scant eosinophilic cytoplasm. Bar=50 µm.

On Day 27, it was confirmed that vomiting had resolved, activity and appetite had improved, and body weight had increased, although gagging continued. By Day 97, the body weight had increased to 9.98 kg. Subsequently, on Day 413, the owner reported that the gagging had disappeared. However, on Day 487, the owner reported that the frequency of gagging had increased again, although activity and appetite remained normal. On Day 514, CT and magnetic resonance imaging (MRI) were performed to assess the condition of the resection site and possible intracranial tumor invasion. Neither examination revealed significant swelling of the vagus-sympathetic trunk at the resection site or an intracranial lesion, and a mass lesion with unclear margins on the left ventricular free wall was identified as an incidental finding. The owner declined further investigations or treatments.

To our knowledge, there are only four previous reports on canine cases of malignant PNSTs originating from the vagus nerve. The first case was a dog diagnosed with a malignant PNST originating from the right vagus nerve in the thoracic cavity, presenting with hypertrophic pulmonary osteoarthropathy. Following resection of the affected vagus nerve at the tumor site, limb swelling, lameness, and pruritus resolved. At the time of reporting, the dog had survived for 710 days postoperatively [4]. The second case was a dog diagnosed with a malignant PNST originating from the right vagus-sympathetic trunk at the ventral aspect of the third cervical vertebra. The dog presented with chronic vomiting, gagging, coughing, dyspnea, lethargy, weight loss, Horner’s syndrome, and ipsilateral laryngeal paralysis. The dog’s general condition at the time of presentation was poor, and the dog was euthanized without any treatments [9]. The third case was a dog diagnosed with a malignant PNST originating from the left vagus-sympathetic trunk. The dog had a six-month history of coughing, retching, salivation, and left-sided Horner’s syndrome. Following resection of the affected vagus-sympathetic trunk, all clinical signs resolved except for Horner’s syndrome. At the time of reporting, the dog had survived for 19 months [11]. The fourth case was a dog diagnosed with a malignant PNST extending from the medulla oblongata to the caudal part of the vagus-sympathetic trunk. The PNST caused compression of the brainstem, resulting in multiple cranial nerve dysfunctions. The dog’s general condition at the time of presentation was poor, and the dog was euthanized at the owner’s request [2]. In the present case, the dog suffered from a malignant PNST originating from the left vagus-sympathetic trunk, and the clinical signs included notable gagging, which occurred several dozen times a day, and chronic vomiting. Although the tumor was incompletely resected, the vomiting resolved, and the general condition significantly improved after the surgery. The findings in the previous reports and the present case suggest that dogs with malignant PNST in the vagus nerve show different pathophysiological characteristics depending on their site of origin. In particular, malignant PNSTs originating from the vagus-sympathetic trunk cause upper gastrointestinal signs, such as gagging and vomiting.

The pathophysiology in the present case is difficult to clarify; however, it is highly likely that both gagging and vomiting were caused by the neurological abnormalities of the vagus nerve due to the tumor. Gagging is a clinical sign caused by morphological or functional abnormalities of the pharynx, airway, or esophagus. Gagging comprises brisk and brief elevations of the soft palate together with bilateral contraction of the constrictor muscles of the pharynx resulting in the ejection of unwanted, irritating, or toxic material [7]. After intraoral stimulation, afferent fibers of the trigeminal, glossopharyngeal, and vagus nerves pass the stimulation to the medulla oblongata. Subsequently, efferent impulses give rise to the spasmodic and uncoordinated muscle movement characteristic of gagging [7]. In the present case, there was no evidence of compression of the pharyngeal region by the mass on CT. Thus, it is reasonable to think that gagging was not caused by a structural abnormality but by abnormal afferent and efferent nerve stimulation by PNST of the vagus-sympathetic trunk, that is, a functional abnormality of the vagus nerve. Gagging observed in this case showed temporary improvement on Day 413, but it was reported to have relapsed on Day 487. CT and MRI at the time of the recurrence of gagging did not show any swelling of the vagus-sympathetic trunk at the site of resection, and the exact cause of the recurrence remains unclear. Gagging is a reflex mediated by the afferent fibers of the trigeminal, glossopharyngeal, and vagus nerves, as well as the efferent fibers of the vagus nerve. In the present case, the PNST was located on the caudal side of the pharynx and the efferent vagus nerve fibers controlling the pharynx were preserved postoperatively. Therefore, it was hypothesized that residual tumor cells due to incomplete resection might reactivated the afferent stimulation to the medulla, which induced the recurrence of sustained efferent stimulation of the bilateral vagus nerves controlling the pharynx, leading to continuous triggering of gagging. However, it is still unknown why the long duration was needed from the surgery to the improvement of the clinical sign of gagging in the present case.

Vomiting physiology is also closely associated with the vagus nerve. Stimuli received in the duodenum are transmitted to the brainstem via afferent fibers of the vagus nerve. This stimulus is then conveyed to the stomach through efferent fibers of the vagus nerve. These transmitted signals stimulate gastric motility and glands within the gut wall, which promotes the secretion of gastrin. Gastrin, in turn, stimulates acid secretion and gastric motility [5]. A previous report documented a case of vomiting associated with PNST of the vagus-sympathetic trunk [9]. In the present case, vomiting completely resolved after surgery although the resection was incomplete, and it was hypothesized that severing of the vagus nerve on the affected side interrupted the neural transmission involved in vomiting. This disruption likely led to a reduction in both afferent input to the brainstem and efferent stimulation of the gastrointestinal tract, which may have contributed to the resolution of vomiting.

A previously reported case with PNST of the vagus-sympathetic trunk had shown no evidence of metastasis, and complete resection of the tumor had led to improvements of clinical signs, with survival of up to 19 months confirmed at the time of reporting [11]. In contrast, in the present case, the tumor was incompletely resected; however, the vomiting completely resolved, the other clinical signs of the case improved significantly, and the case achieved an overall survival of at least 514 days at the time of reporting. These observations suggest that, even if complete resection is not feasible, aggressive surgical resection may still improve the clinical signs and prognosis of the case with PNST of the vagus-sympathetic trunk. PNSTs are generally considered to have a high risk of local recurrence following surgical resection, and the relapse-free interval, defined as the duration from diagnosis to either histological confirmation of tumor recurrence or the onset of clinical signs suggestive of recurrence, has been reported to be approximately 7.5 months for tumors originating from the plexus nerve and 1.0 month for those originating from nerve roots [1]. However, another study reported that the median recurrence-free interval, defined as the interval between the date of the surgery and the date of recurrence, was 874 days in PNST cases whose surgical margins were less than 5 mm, and this study also included the cases that underwent incomplete resections [3]. Since tumors of these cases located in the foreleg (n=24), hindleg (n=9), and head or trunk (n=5), it is possible that cases with PNSTs originating from peripheral sites can obtain relatively favorable local control even if complete resections are not achievable as in the present case. However, recurrence of gagging was observed in the present case on Day 487, as previously discussed, and it remains possible that microscopic residual tumor cells had proliferated without the development of any detectable lesions. It should also be noted that the metastasis can develop due to incomplete resection. In the present case, a mass lesion on the left ventricular free wall was observed on the second CT scan. While metastasis of PNST is rare in dogs [8], a previous report showed that the majority (75%) of metastatic lesions in the heart were observed in the left ventricular free wall, the interventricular septum, or both [10]. As the owner declined further investigation, it was unclear whether the mass lesion was a metastasis of PNST or a primary tumor such as hemangiosarcoma or lymphoma in the present study.

In the present report, we described a canine case of malignant PNST originating from the vagus-sympathetic trunk. The dog showed clinical signs including gagging and vomiting similar to previously reported cases, but incomplete resection of the tumor resulted in significant improvement of the clinical signs. The findings obtained from the present case suggest that aggressive surgical resection, even if complete resection is not expected, may be beneficial for dogs with malignant PNST originating from the vagus nerve. It is essential to accumulate knowledge of malignant PNSTs originating from the vagus nerve for a more comprehensive understanding of their pathophysiology and treatment outcome.

CONFLICT OF INTEREST

There is no conflict of interest.