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SMALL INTESTINAL GANGLIONEUROMATOSIS ACCOMPANIED BY AN ULCER IN A 13-YEAR OLD DOG

Ganglioneuromatosis is a rare disorder characterized by hyperplasia of intestinal ganglia including myenteric plexus and enteric nerve fibers. This disorder is generally described in children, but sporadic cases have also been described in adults. Most human cases arise in the colon and rectum. The disorder has also been described in dogs, mostly juveniles, but rarely in mature dogs with the oldest dog reported with this change being 9 years old.


INTRODUCTION
Ganglioneuromatosis is a rare disorder characterized by poorly demarcated, multinodular to diffuse proliferation of intestinal ganglia including myenteric and enteric nerve fibers [1,2]. This disorder is primary a human disease occurring anywhere in the alimentary tract, from the oral cavity to the rectum, but is mostly found in the colon [3,4].
Ganglioneuromatosis has been described in few dogs in the intestinal tract [5][6][7][8] and in the wall of the gallbladder [9]. It has so far been mostly reported in puppies and juveniles [5][6][7], rarely in adult dogs [8,9]. Reported clinical signs of ganglioneuromatosis include persistent diarrhea, intermittent vomiting, poor appetite, depression and poor body condition in small intestinal ganglioneuromatosis [6,8] and tenesmus, hematochezia and rectal prolapse in colorectal ganglioneuromatosis [5,7]. The etiology of the disease in dogs is unknown. In most reported canine cases it was speculated that the lesion was congenital due to young age of the patients and slowly progressive nature of the lesion [5][6][7]. Proposed theories in humans include overexpression of neural growth factor causing proliferation of nerve fibers, hyperplasia of nerve fibers, decreased expression of the tumor suppressor gene and increased expression of glial cell linederived neurotrophic factor and neurturin [10][11][12][13].

CASE REPORT
A 13-year-old female, mixed-breed dog from a shelter was presented to a local veterinarian with a history of diarrhea and weight loss of unknown duration. Ultrasound performed by referring veterinarian revealed focally-extensive markedly thickened segment of the small intestine. The changed part of the intestine was removed on laparotomy and delivered for histopathologic examination fixed in 10% neutral, buffered formalin. Surgery and histologic analysis were allowed by the owner of the dog (animal shelter).
The submitted tissue was a 7 mm x 20 mm part of the small intestine with a thickened wall ( Fig. 1). Focally, there was a linear, dark brown to black colored defect in the mucosa measuring 7 mm in length and less than 1 mm in width. Histology revealed diffuse hyperplasia of myenteric and submucous plexus affecting the submucosa and muscularis of the whole submitted small intestine (Fig. 2). The cell bodies were polygonal in shape, with a large round to oval nucleus with coarse to vesicular chromatin and one pronounced nucleolus (Fig. 2 inset). The cytoplasm was eosinophilic, scant and with faintly to moderately visible cell borders. Neurons were surrounded by elongated cells with moderate to abundant eosinophilic, fibrillar, sometimes foamy, cytoplasm compatible with Schwann cells (Fig. 2 inset). The linear defect, seen grossly, was expanding from the mucosa to the proximal half of the circular layer of the muscularis and characterized by necrosis of all affected layers and accumulation of predominantly neutrophils and smaller number of macrophages, lymphocytes and plasma cells (Fig. 3). Around the defect were activated fibroblasts.
Histologic findings were consistent with ganglioneuromatosis and focally extensive, subacute intestinal ulcer.
The veterinarian submitting the tissue was contacted for follow-up at the time of writing of this manuscript (6 months after surgery). The dogs' recovery from surgery was uneventful, and the dog was doing well, without any therapy. Gastrointestinal signs reported at presentation ceased after surgical removal of the affected intestine.
So far, ganglioneuromatosis was reported predominantly in young dogs [5][6][7], rarely in adults [8,9]. The oldest reported dog with ganglioneuromatosis was 9 years old [8]. Our report shows that ganglioneuromatosis can also be encountered in older dogs, as our dog was 13 years old at the time of presentation.
Radiographic or ultrasound examination may be useful in localizing the affected intestine, which is usually thickened due to accumulation of hyperplastic nerve cells [2,6]. Histologic examination of full thickness biopsy or completely excised affected tissue is required to make a definitive diagnosis of ganglioneuromatosis [6]. Immunohistochemical markers of nerve tissue (neurofilament protein, neuronspecific enolase and synaptophysin) can highlight ganglion cells and aid in diagnosis [6]. Diagnosis in this case was set based only on histology as the shelter caring for the dog declined immunohistochemical staining.
From the histologic findings and the clinical picture, it is not clear whether ganglioneuromatosis and the intestinal ulcer were associated lesions or presented independent pathology in the current dog. The intestinal ulcer was a localized lesion, and although presumably painful for the animal, was probably not the cause of intestinal signs, as only a small area of the intestine was affected. As the ganglioneuromatosis affected the whole intestinal biopsy of the intestine, we presumed that this was the primary cause of intestinal signs.
In summary, ganglioneuromatosis is a rare disorder of the gastrointestinal nervous system causing vomiting and diarrhea in dogs. Although a rare occurrence, this disorder should be considered as a differential diagnosis in dogs with diarrhea, when common infectious and neoplastic causes have been ruled out.

Ethical approval
The conducted research is not related to animals use. No ethical approval was obtained because this study did not involve laboratory animals and only involved tissue obtained as a product of surgery used as treatment of the diseased animal.