Signalment:  

1-year-old, male, Beagle dog.This dog was part of a 10-day oral toxicological study and was euthanized at the end of the study. There were no relevant clinical signs

Gross Description:  

An abnormal shape of the cecum was the only relevant macroscopic finding. 

Histopathologic Description:

There is invagination of the tip of the cecum within its lumen. All parts of the cecum wall are diffusely, moderately thickened (about twice normal thickness). The muscularis mucosa, the submucosa, some parts of the muscular layers (particularly the longitudinal layer), and the serosa are replaced by a poorly demarcated tissue, primarily in the same location as the myenteric (Auerbachs) and the submucous (Meissners) plexuses (Fig. 3-1). This tissue is composed of irregularly-arranged wavy fascicles of nerve fibers with round and spindle cells, and some clusters of enlarged ganglion cells (Fig. 3-2). The mucosa is moderately hyperplastic, with multifocal to coalescing hemorrhages in the lamina propria, and multifocal minimal degeneration of some glands. Scattered in the submucosa and the proliferative neural tissue are some cells containing large pigmented brown granules (hemosiderin).

Morphologic Diagnosis:  

Cecum: Transmural ganglioneuromatosis, locally extensive, with intussusception.

Lab Results:  

There were no significant findings

Condition:  

Gangioneuromatosis

Contributor Comment:  

Intestinal ganglioneuromatosis refers to a hyperplastic proliferation of ganglion cells, nerve fibers, and supporting cells of the enteric nervous system. In humans, intestinal ganglioneuromatosis is most often part of multiple tumor syndromes, particularly the multiple endocrine neoplasia (MEN) 2B syndrome.¹² MEN-2B is inherited in an autosomal dominant fashion and is caused by a single mutation in the RET proto-oncogene. This heritable endocrine disorder is characterized by medullary thyroid carcinoma, pheochromocytoma, multiple mucosal neuromas, gastrointestinal ganglioneuromatosis, corneal nerve thickening and skeletal abnormalities.⁸ Gastrointestinal symptoms are common in patients with MEN-2B, and are secondary to the pseudo-obstruction caused by the ganglioneuromatosis.⁶ The pathogenesis of ganglioneuromatosis is not well understood, but some studies in humans indicate that it may be related to the overproduction of some nerve growth factors. 

Immunohistochemically, some cases of ganglioneuromatosis were shown to be a complex hyperplasia of several peptidergic, cholinergic, and probably adrenergic nerve fibers instead of a selective overgrowth of one type of nerve fibers.⁴

Some rare cases of intestinal ganglioneuromatosis or ganglioneuromas have been reported, most often in young animals: in a horse¹, a steer³, a cat⁹, and 3 dogs.^5,11,13 In all cases, there were clinical signs (e.g. colic, impaction, anorexia, vomiting, diarrhea, rectal prolapse) that led to surgical resection of the masses. Masses were located in the small intestine (3 cases), colon (1 case), colorectum (2 cases) or Vaters papilla (1 case). This is the first reported case of asymptomatic ganglioneuromatosis in a dog. 

JPC Diagnosis:  

Cecum (per contributor): Ganglioneuromatosis, with intussusception, Beagle (Canis familiaris), canine.

Conference Comment:  

Ganglioneuromas are composed of mature autonomic ganglion cells, satellite cells, unmyelinated and occasionally myelinated axons, Schwann cells and a fibrous stroma. They are generally considered benign neoplasms. Intestinal ganglioneuromatosis is considered a hyperplasia of similar elements; it is typically transmural. As noted by the contributor, both lesions are rare in animals and have not been found to be associated with MEN-like syndromes.⁷ Some have suggested that ganglioneuromas may actually represent hamartomas (benign, nonneoplastic, tumor-like nodules consisting of an overgrowth of mature cells that normally occur in the affected organ) rather than benign neoplasms.¹⁰

Intussusceptions are described as having three layers: (1) outer wall of the receiving segment, (2) middle returning segment of invaginated bowel, and (3) inner entering segment. The intussusception seen in this lesion is unusual in that it contains only two of the three layers, a feature that will occur only through the invagination of a blind pouch (in this case, the tip of the cecum). Cecal inversion is another term for such a lesion (Fig. 3-3). Various causes of intussusception may include linear foreign bodies, heavy parasitism, previous intestinal surgery, enteritis, and intramural lesions. It may also develop as a terminal, agonal or postmortem event.²


Fig 3-3
A. Intussusception of tubular section of bowel consisting of three layers: (1) outer wall of the receiving segment, (2) middle returning, segment of invaginated bowel, and (3) inner entering segment. 
B. Intussusception of a blind pouch consisting of two layers: (1) outer wall of the receiving segment, and (2) the middle returning, segment of invaginated bowel.

We appreciate the assistance from the Departments of Gastrointestinal Pathology, Neuropathology, and Soft Tissue Pathology at the Armed Forces Institute of Pathology in consultation on this case.

References:

1. Allen D, Swayne D, Belknap JK: Ganglioneuroma as a cause of small intestinal obstruction in the horse: a case report. Cornell Vet 79:133-141, 1989
2. Brown CC, Baker DC, Barker IK: Alimentary system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 2, pp. 96-97. Elsevier Limited, St. Louis, MO, 2007
3. Cole DE, Migaki G, Leipold HW: Colonic ganglioneuromatosis in a steer. Vet Pathol 27:461-462, 1990
4. DAmore ES, Manivel JC, Pettinato G, Niehans GA, Snover DC: Intestinal ganglioneuromatosis: mucosal and transmural types. A clinicopahologic and immunohistochemical study of six cases. Hum Pathol 22:276-286, 1991
5. Fairley RA, McEntee MF: Colorectal ganglioneuromatosis in a young female dog (Lhasa Apso). Vet Pathol 27:206-207, 1990
6. Goyal RK, Hirano I: The enteric nervous system. N Engl J Med 334:1106-1115, 1996
7. Head KW, Else RW, Dubielzig: Tumors of the alimentary tract. In: Tumors in Domestic Animals, ed. Meuten DJ, 4th ed., p. 470. Blackwell Publishing, Ames, IA, 2002
8. Komminoth P: Multiple endocrine neoplasia type 1 and 2: from morphology to molecular pathology. Vehr Dtsch Ges Path 81:125-138, 1997
9. Patnaik AK, Lieberman PH, Johnson GF: Intestinal ganglioneuroma in a kitten a case report and review of literature. J Small Anim Pract 19:735-742, 1978
10. Porter BF, Storts RW, Payne HR, Edwards JF: Colonic ganglioneuromatosis in a horse. Vet Pathol 44:207-210, 2007
11. Ribas JL, Kwapien RP, Pope ET: Immunohistochemistry and ultrastructure of intestinal ganglioneuroma in a dog. Vet Pathol 27:376-379, 1990
12. Shekitka KM, Sobin LH: Ganglioneuromas of the gastrointestinal tract. Relation to Von Recklinghausen disease and other multiple tumor syndromes. Am J Surg Pathol 18:250-257, 1994
13. Van Den Ingh TSGAM, Rothuizen J: Ganglioneuroma of Vaters papilla and extrahepatic cholestasis in a dog. Vet Pathol 21:254-256, 1984

A virtual slide is not available for this case.

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(Fig 3-1) Cecum

(Fig 3-2) Cecum

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