Introduction

Reports of hamartomatous ganglioneuromatosis in veterinary medicine are rare and isolated to few case reports. There is little known about this condition other than what has been extrapolated from cases in humans. Diagnosis of this condition may be challenging, and long-term follow-up of cases are not well documented.

Case Report

A 4 mo old male goldendoodle presented for evaluation of chronic hematochezia with a history of recurrent rectal prolapse and chronic tenesmus. Six weeks before presentation, the puppy had been evaluated by the referring veterinarian following three episodes of recurrent rectal prolapse. In each case, the protruding tissue was described as a prolapse, not an intussusception. Each time the prolapse was manually reduced and a purse string suture placed; the prolapse recurred 1 wk later following suture removal. After suture removal following the third purse string suture placement, the rectum did not prolapse, but hematochezia, tenesmus, and diarrhea persisted. A fecal examination revealed Giardia, and the puppy was treated by his veterinarian with oral metronidazole for 10 days (dosage not available). Other treatments included a diet change to Royal Canine GI Puppy food, an unknown generic deworming product, and prednisone (0.25 mg/kg per os (PO) twice daily).

On presentation, the puppy was in normal body condition with no abnormalities on general physical examination. Complete blood count revealed leukocytosis (17.71 × 10³/μL, reference range 5.0–4.2 × 10³/μL) characterized as a mature neutrophilia. Serum chemistry panel revealed elevated alanine transaminase (325 U/L, reference range10–90 U/L), elevated alkaline phosphatase (450 U/L, reference range 11–140 U/L), mild hypercalcemia (11.4 mg/dL, reference range 8.8–11.2 mg/dL), mild hyperphosphatemia (7.1 mg/dL, 2.5–5.0 mg/dL), and slightly decreased creatinine (0.44 mg/dL, reference range 0.5–1.4 mg/dL). Serum trypsin-like immunoreactivity, pancreatic lipase immunoreactivity, cobalamin, and folate were all within normal limits. Fecal flotation was negative, and urinalysis was unremarkable.

Radiographs of the abdomen (Figure 1A) revealed a focal 3.6 cm dilation of the mid-descending colon filled with heterogenous soft-tissue opaque material and mild hepatomegaly. Abdominal ultrasound revealed a telescoping loop of colon (consistent with an intussusceptum) within a dilated loop of colon (consistent with an intussuscipiens) in the descending colon. Hyperechoic mesentery dissecting between the intussusceptum and intussuscipiens displayed blood flow on color Doppler interrogation (Figure 1B). Patsikas et al. report that intussusceptions in young dogs are surgically reducible 75% of the time when color flow Doppler signal is observed indicating blood flow to the mesentery of the intussuscepted intestine.¹ Based on the diagnostic imaging findings, surgery to explore the abdomen and to reduce the intussusception was recommended.

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Anesthesia was induced using propofol (2 mg/kg IV) and midazolam (0.1 mg/kg IV) to effect, following premedication with methadone (0.2 mg/kg IV) and maropitant (1 mg/kg IV). Preoperative cefazolin was administered (22 mg/kg IV). The patient was intubated and maintained on isoflurane and oxygen. An intraoperative fentanyl (5 μg/kg/hr)/lidocaine (40 μg/kg/min)/ketamine (0.6 mL/hr) constant rate infusion was provided.

A celiotomy was performed, and an approximately 5 cm long intussusception was identified in the descending colon. The intussusception was reduced using gentle traction. A thick, fibrous, broad-based 3.5 cm soft-tissue mass was appreciated within the intussusceptum. On palpation, the mass was flat, discoid, nonmovable, and was felt to originate within the intestinal wall. A colotomy was performed, and the mass was exteriorized for greater visualization. The mucosa was intact, and the mass was observed to be flat, round, and intramural. Colonic resection and anastomosis were performed by occluding the colon oral and aboral to the mass with an assistant’s fingers. Fecal material was milked away from the colectomy site. After ligating and transecting individual vessels to the proposed colectomy site, the colon was sharply transected, and an anastomosis was performed using 3-0 polydioxanone suture Plus simple interrupted sutures. The mass and 2 cm of grossly normal tissue margins orally and aborally were excised. Following anastomosis, the colon was leak tested using saline. Additional intraoperative findings included mild mesenteric lymphadenopathy. Biopsies of the stomach, duodenum, jejunum, ileum, and mesenteric lymph nodes were also collected. The puppy recovered from surgery uneventfully. Postoperative care included maintenance IV fluids (60 mL/kg/day), maropitant (1 mg/kg/day IV), pantoprazole (1 mg/kg/day IV), trazodone (5 mg/kg PO q 8 hr), Acetaminophen/codeine (1.4 mg/kg PO q 8 hr), amoxicillin/clavulanic acid (13.75 mg/kg PO q 12 hr), and metronidazole (11.4 mg/kg PO q 12 hr). Because of regurgitation and aspiration during the postoperative period and the following day, the puppy received treatment by nebulization and coupage with supplemental oxygen. Ten days after the operation, the puppy was discharged from the hospital.

Histopathology of the colonic mass revealed markedly hyperplastic submucosal and myenteric plexi. The submucosa and mucosa were infiltrated and expanded by interweaving fascicles of spindle cells with moderate amounts of streaming eosinophilic cytoplasm and plump oval nuclei with finely stippled chromatin and inconspicuous nucleoli (Schwann cells) that extended from and were continuous with hyperplastic submucosal plexi, multifocal hyperplastic myenteric plexi, and intermingled with bands of collagenous fibrous stroma. Numerous small polygonal cell clusters and individual large polygonal cells with abundant eosinophilic cytoplasm containing stippled basophilic material (Nissl substance) and large round vesicular nuclei with a single prominent nucleolus (neuronal cell bodies) were intermixed with the spindle cell population (Figure 2A, B). Neuronal cell bodies were frequently surrounded by small spindle cells with scant amounts of eosinophilic cytoplasm and small hyperchromatic oval nuclei (glial cells). Neuronal cell bodies were stained positively with neuron-specific enolase (Figure 2C). Schwann cells and glial cells were stained positively with glial fibrillary acid protein, and collagenous stroma was negative for glial fibrillary acid protein (Figure 2D).

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The colonic mucosa was markedly distorted by infiltrative Schwann cells, neuronal cells bodies, and glial cells that dilated and distorted colonic glands. Glands were lined by attenuated epithelium and contained amorphous eosinophilic material, mucinous debris, and occasional degenerate cells. There were moderate numbers of degenerate neutrophils, lymphocytes, plasma cells, and hemosiderin-laden macrophages throughout the mass and mucosa. There was moderate hemorrhage and edema of the superficial mucosa. The submucosal lymphatic and blood vessels were moderately dilated and congested. Hyperplastic myenteric ganglia and lamina propria infiltration extended to the oral surgical margin. Findings in the gastrointestinal biopsies were consistent with mild lymphoplasmacytic enteritis.

The puppy was re-evaluated 2 wk after surgery. The owners noted that he continued to have soft stools, but the consistency was approaching normal. They had observed one episode of tenesmus since surgery, but no hematochezia was appreciated. The puppy appeared clinically normal on physical examination, and his surgical incision had healed well.

At the 12 wk postoperative surgical recheck examination, the puppy’s bowel movements had returned to normal consistency with no hematochezia and infrequent episodes of tenesmus. The physical examination was within normal clinical limits. Recheck abdominal ultrasound examination revealed that the colonic anastomosis site was well healed, and the colon appeared otherwise normal. No masses were observed during this examination.

The puppy was rechecked a final time 11 mo after surgery. He had since been neutered (per recommendation) and was reported to have normal stools with no episodes of tenesmus. Physical examination was again normal. The radiographs of his abdomen were unremarkable. An abdominal ultrasound revealed no masses and a normal appearing colon. because of the paucity of long-term clinical case information for patients with this type of tumor, the follow-up recommendations for this patient included yearly abdominal screening ultrasound examinations to monitor for development of intra-abdominal masses.

The owner reported by phone follow-up 14 mo after surgery that the dog was doing well clinically. No tenesmus, dyschezia, or hematochezia were reported, and the dog was thriving. No other abnormal clinical findings were reported by the owner.

Discussion

A hamartoma is a benign tumor-like lesion composed of a disorganized overgrowth of cells occurring in a normal anatomical location that is most often congenital. Gastrointestinal hamartomatous polyps are sessile or pedunculated masses composed of normal cells arranged in a disarrayed architecture typically arising from and restricted to the intestinal mucosa.^2–4 Hereditary polyposis syndromes in people are characterized by the presence of adenomatous or hamartomatous polyps and are inherited in an autosomal dominant pattern.⁵ Mutations in the PTEN tumor suppressor gene may result in polyposis syndromes including Cowden’s syndrome. Approximately 85% of humans with Cowden’s syndrome carry a mutation of the PTEN tumor suppressor gene, which normally inhibits cell growth and proliferation. In people, mutations in this gene show a potential for increased risk of malignant neoplasia, including cancer of the breast, thyroid, and uterus.⁵

The changes seen in the colon of the puppy in our case were most consistent with colonic hamartomatous ganglioneuromatosis given the presence of markedly hyperplastic submucosal and myenteric plexi (ganglia), infiltration and expansion of the mucosa and submucosa, and poor delineation along the oral surgical margin. The changes seen in the other submitted tissues of this case were attributed to intussusception and intermittent rectal prolapse as observed clinically. A hamartomatous ganglioneuroma is a congenital lesion often associated with a mutation in the PTEN gene in people. People with this condition are predisposed to the formation of multiple endocrine neoplasia syndrome associated with Cowden Syndrome.^6,7

Ganglioneuromatoses in people are categorized as one of three types of presentations. The most common of which is the presence of a solitary ganglioneuroma. Ganglioneuromas are typically <2 cm in diameter polypoid or sessile and are not associated with systemic or genetic disorders. A second type of presentation of ganglioneuromas, known as ganglioneuromtasosis polyposis, is when multiple (>20), small (ranging from a few millimeters to ≤2 cm), pedunculated or sessile polyps are present.^8,9 A third presentation is diffuse ganglioneuromatosis These are larger (1–17 cm), nodular masses that involve the myenteric plexus. Histologically, these masses contain diffuse hyperplastic expansion of the myenteric plexi or may resemble an irregular transmural ganglioneuroma.^8,10,11

Because of the genetic basis for development of ganglioneuromatosis and polyposis syndromes in humans with diffuse ganglioneuromatosisand and the scarcity of information about this in clinical veterinary cases, the owner of the puppy in this case was advised to closely monitor this puppy for other tumor-like lesions. It was also advised that the puppy not be bred, and the breeder be notified of the diagnosis to prevent propagation of a potential genetic mutation. There is a paucity of long-term case reports in dogs with ganglioneuromatosis; therefore, it is largely unknown if dogs share a genetic predisposition for tumor development as demonstrated in humans. There was not any available information about littermates of this puppy and whether they had similar lesions nor was genetic testing performed on the puppy in this case. As such, the prudent recommendations to monitor this puppy and to not breed this patient were made.

Reports of hamartomatous ganglioneuromatosis in veterinary medicine are extremely rare, isolated to only a few case reports. Little is known about this condition other than what has been extrapolated from cases in humans. A 5 mo old Great Dane puppy diagnosed with colorectal hamartomatous ganglioneuromatosis was reported with similar clinical and histological findings as the puppy in this case. This dog’s lesions were most consistent with diffuse ganglioneuromatosis characterized by mural thickening with polypoid mucosal nodules in the colon and rectum. Genomic DNA from these lesions revealed PTEN mutation similar to that seen in Cowden’s syndrome in humans. Unfortunately, that puppy died of gastric dilatation-volvulus 1 yr after surgery, and follow-up information was unavailable. A necropsy was not performed on this patient, so it is not known whether any concurrent intra-abdominal pathology contributed to this event.⁶

A 12 mo old Lhasa apso was diagnosed with colorectal ganglioneuromatosis of the colon with lesions present in the submucosa and muscluaris layers. This dog was treated by subtotal colectomy, but dehiscence of the anastomosis site ensued, and the puppy was euthanized. That dog similarly presented with hematochezia, tenesmus, and recurrent rectal prolapse. Histologically, the lesions in that dog and the puppy in this case were similar. No genetic testing of this tissue was performed.⁷

A rectal ganglioneuroma in an 18 mo old Australian terrier cross was successfully resected following presentation for chronic large bowel diarrhea. Clinically, this dog had two mucosal masses of the distal large intestine (5 and 10 mm) that were ulcerated. The masses were locally resected, and the histopathologic diagnosis revealed ganglioneuromas. Ganglioneuromas are rare tumors in the gastrointestinal tract of neuroblastic origin composed of a combination of ganglion cells, nerve fibers, Schwann cells, and neuroblasts forming a discrete mass. At the time of writing, the dog in that case had survived and was reported to be clinically normal 2.5 yr after surgery. Genetic testing of the affected tissue was not performed.¹²

It has been suggested in several studies that young puppies are more likely to be diagnosed with intussusceptions.¹³ In one study including 153 dogs surgically treated for intestinal intussusceptions, the reported median age was 10 mo.⁴ Clinical signs associated with intussusceptions include vomiting, diarrhea, anorexia, lethargy, and hematochezia.⁴ Signs can vary depending on the location of the intussusception. Large intestinal intussusceptions may present with hematochezia and tenesmus, whereas small intestinal intussusceptions may present with vomiting and anorexia. Prolapse through the rectum is a recognized complication associated with colonic intussusceptions, and a blunt probe can be used to help differentiate a rectal prolapse from a prolapsed colonic intussusception. If the probe passes into the rectum without meeting resistance, then it is likely a prolapsed intussusception. If the probe is unable to pass into the rectum, it is a likely a rectal prolapse.¹⁴

Conclusion

Much about the clinical behavior of ganglioneuromatosis remains unknown in small animals because of the rarity of this type of lesion and the lack of long-term follow-up in these patients. Recommendations for long-term cancer screening are attributed to those cases described in people. Genetic testing in this puppy was not performed, and the owner planned to have the dog castrated. Confirmation of a PTEN gene mutation would be useful in terms of prognosis for this patient and others in the future but was not performed in this case. However, as previously stated, it is still unknown how predictive that information would be and if the clinical behavior of ganglioneuromatosis in dogs would be comparable to that in humans without genetic testing, additional cases, and until long-term data become available. This report should serve as a reminder to include this lesion as a rare differential diagnosis for colorectal masses in dogs.