Diffuse intestinal ganglioneuromatosis in a child

Abstract

A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia.

Ganglioneuromas are benign neurogenic tumors often diagnosed in children. While they typically develop from sympathetic ganglia and adrenal glands, some arise from the viscera. Intestinal ganglioneuromas are rare and consist of 3 subgroups: 1) solitary polypoid ganglioneuromas, 2) ganglioneuromatous polyposis, and 3) diffuse ganglioneuromatosis [1]. Intestinal ganglioneuromatosis often leads to thickening of the bowel wall leading to stricture formation, abdominal pain and diarrhea [2]. Diffuse ganglioneuromatosis is typically associated with several diseases including neurofibromatosis-1 (NF1), Cowden syndrome (CS), and most frequently multiple endocrine neoplasia type 2B (MEN 2B) [2]. In this report, we describe a case of diffuse intestinal ganglioneuromatosis in a 7 year old patient with congenital neutropenia.

1. Case report

A 7 year old male with a past medical history significant for chronic neutropenia and growth hormone deficiency, had a 2 week history of abdominal pain, nausea, and decreased oral intake leading to a diagnosis of colitis. He presented to the emergency department with a 2 day history of increasing abdominal pain, right-sided abdominal fullness, diarrhea, and hematemesis. His physical examination was remarkable for diffuse tenderness to palpation. Acute abdominal series demonstrated several mildly dilated loops of small bowel with air fluid levels, and a relative paucity of bowel gas in the right lower abdomen. CT scan of the abdomen revealed significant ascending colonic wall thickening with fat stranding, and extensive fatty proliferation around the ascending colon (Fig. 1). In addition, there was mild distention of the cecum and ascending colon. Diagnostic laparoscopy revealed significant thickening of mesenteric fat that wrapped around the anterior surface of the ascending colon. Esophagogastro-duodenoscopy (EGD) revealed moderate esophagitis, and colonoscopy showed stenosis in the ascending colon with edematous and pale mucosa. Endoscopic colonic biopsy specimens revealed focal epithelial hyperplasia, edema and expansion of the lamina propria, and patchy mucosal hemorrhage.

Fig. 1.

CT scan of the abdomen. Shown are: (A) axial, (B) coronal and (C) sagittal reconstructed images from the abdominal CT scan. Each image demonstrates marked wall thickening of the ascending colon. The surrounding fat is abnormal and more extensive than is seen with Crohn’s Disease. In addition, there is stranding within the fat extending from the ascending colonic serosa, the mucosal surface is nodular and irregular, and the lumen of the colon is narrowed with proximal bowel dilation.

Resection of the ascending colon and 4 cm of the distal ileum was performed, with a stapled side-to-side functional end-to-end ileocolonic anastomosis performed in grossly normal appearing bowel. Pathologic examination of the specimen revealed prominent proliferation of thick nerve fibers with ganglion cells in the submucosa that extended focally through the muscular coat into the subserosal bowel wall, consistent with a diagnosis of diffuse intestinal ganglioneuromatosis. The ileum, appendix, and cecal margin had mildly increased numbers of enlarged nerve fibers along with ganglion cells in the muscular coat and subserosa. There was microscopic disease at the resection margins. Subsequently, serum and urine metanephrine and normetanephrine levels were obtained but were not consistent with the presence of pheochromocytoma. Genetic testing for the RET protooncogene mutation, and deletions in the NF1 and PTEN genes were performed and were also negative.

The patient’s post-operative course was notable for several admissions for colitis and gastroenteritis. Several months later, a CT scan of the abdomen showed thickening of the distal ileum at the anastomotic site with fatty proliferation and fat stranding, raising the possibility of recurrent tumor. EGD and colonoscopy revealed gastritis and stenosis at the ileocolonic anastomosis, respectively. He was returned to the operating room 7 months after the initial resection where he underwent resection of the ileocolonic anastomosis with a side-to-side functional end-to-end ileocolonic anastomosis performed in healthy appearing bowel. Pathologic examination confirmed the frozen section diagnosis of diffuse ganglioneuromatosis in both the small bowel and colon at the resected anastomotic site, this time with microscopically negative resection margins (Fig. 2). Further genetic testing was performed and was negative for mutations in the NF1 and PTEN tumor suppressor genes. The patient is now 16 months after his second resection and continues to have admissions for fevers, abdominal pain, and diarrhea, with repeat imaging intermittently showing inflammatory changes and bowel wall thickening at the site of the anastomosis. A colonoscopy was recently performed and biopsies obtained showed inflammation at the anastomosis but no evidence of recurrence. Further surgery has not been required to date.

Fig. 2.

Histologic and immunohistochemical examination of specimen from second resection. (A) The lesions in the colon are inconspicuous at low magnification. H&E, 20× magnification. (B) At higher magnification, the submucosa is seen to contain numerous large abnormal nerve bundles (bracket). H&E, 100× magnification. (C) Abnormally arranged aggregates of ganglion cells are closely associated with the nerve bundles of the lesion. H&E, 400× magnification. (D) Immunohistochemical staining for S100 highlights the abnormal nerve bundles in the submucosa (arrow) and the associated abnormal ganglion cells (inset), as well as increased numbers of nerve fibers within the muscular wall (bottom half) and the submucosa (top, between glands). The nerve bundles of the lesion are considerably larger than those in the normal ganglia of the myenteric plexus (bracket). 100× magnification. Inset; 400× magnification of area marked with arrow.

2. Discussion

Intestinal ganglioneuromas are rare, benign neurogenic tumors that are more often identified in adults and are divided into 3 subgroups: 1) solitary polypoid ganglioneuromas that are typically asymptomatic tumors of the mucosa and submucosa with features similar to adenomas or juvenile polyps; 2) ganglioneuromatous polyposis characterized by multiple small mucosal polyps comprised of loose collections of mature ganglia, often resembling familial adenomatous polyposis and typically found in the colon and terminal ileum; and 3) diffuse ganglioneuromatosis characterized by hyperplasia of the submucosal and myenteric nerve plexuses with invasion of the bowel wall by ganglioneuromatous tissue [1,2]. The latter form of the disease is usually found in the colon, terminal ileum, and appendix, although adjacent bowel can be involved. Diffuse intestinal ganglioneuromatosis often causes significant bowel wall thickening, submucosal nodularities, and strictures, leading to severe abdominal pain and diarrhea. Due to poor response to medical management, the standard treatment is surgical resection of the diseased bowel as well as a work-up for any associated syndromes [2].

During both operations, a side-to-side functional end-to-end stapled ileocolonic anastomosis was created. During the first operation, the pathology was completely unknown and the resected specimen included intestine affected by palpably gross disease, with what later turned out to be microscopically positive resection margins. At the second operation, when the disease entity was known, somewhat larger margins both proximally and distally were obtained, and the resection margins were negative for disease. Although no disease recurrence has occurred to date, the possibility of recurrence has been discussed with the family, and will be watched for carefully. Since this disease can occur or recur anywhere in the GI tract, we do not feel that frozen section examination of the margins in the operating room is absolutely necessary, and should be left to the discretion of the operating surgeon. Similar to Crohn’s disease, it is likely important to limit the lengths of resection when possible, since future resections may be needed and the development of short gut syndrome needs to be avoided.

As intestinal ganglioneuromas have been associated with several diseases (Table 1), the involvement of a genetics counselor in patients with this disease is essential. Due to an earlier diagnosis of G6PC3 deficiency with congenital neutropenia, the patient discussed here already had an established relationship with a genetics counselor. Intestinal ganglioneuromatosis is most often found in patients with MEN 2B, a rare, autosomal dominant syndrome associated with medullary thyroid carcinoma (MTC) in young children. Other manifestations include pheochromocytoma, mucosal neuromas, and a marfanoid habitus [3]. Several case reports have described the diagnosis of intestinal ganglioneuromatosis in infants associated with MEN 2B [4–7]. In the case described here, the patient did not exhibit any other characteristics of MEN 2B, genetic testing was negative for mutations of the RET protooncogene, and serum and urine vanillylmandelic acid (VMA) and metanephrine levels were negative, suggesting no evidence of pheochromocytoma. When MEN 2B is suspected in an individual, thyroid ultrasounds should be performed to screen for medullary thyroid carcinoma, however, many recommend prophylactic thyroidectomy if a patient is found to be positive for RET mutations.

Table 1.

Disorders associated with intestinal ganglioneuromas.

Disorder	Genetic Abnormality	Manifestations	Management
MEN 2B	RET mutation (M918T mutation in exon 16); autosomal dominant, although 50% arise spontaneously	Medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, marfanoid habitus and other skeletal abnormalities	Early total thyroidectomy
NF1	NF1 mutation (17q11.2); autosomal dominant, although 50% arise spontaneously	Cutaneous neurofibromas, café-au-lait macules, skin-fold freckling, Lisch nodules, subcutaneous and plexiform neurofibromas, macrocephaly, short stature and other skeletal abnormalities, generalized hyperpigmentation, tumors, neurologic abnormalities, cardiac abnormalities, vasculopathies	Symptomatic
Cowden Syndrome	PTEN mutation (tumor suppressor gene); autosomal dominant	Hamartomas, macrocephaly, gastrointestinal polyps, characteristic mucocutaneous lesions; benign or malignant breast, thyroid, endometrial manifestations	Symptomatic; increased cancer surveillance

Intestinal ganglioneuromatosis is also seen in patients with NF-1 (von Recklinghausen disease), an autosomal dominant disorder that occurs in 1:3500 individuals at birth [8,9]. While there have been many documented cases of diffuse ganglioneuromatosis in patients with MEN 2B, its association with NF1 is far more infrequent and typically identified in the adult population [10,11]. Tumors associated with the disease include optic gliomas, retinal hamartomas, and malignant peripheral nerve sheath tumors. Appropriate surveillance for individuals with NF-1 includes an annual physical exam with particular attention to blood pressure changes and bone abnormalities until 10 years old, annual eye exams until 8 years old, and frequent pain assessments. Female patients should be educated on the use of estrogens and oral contraceptives, as they can increase the size or number of neurofibromas. Radiologic imaging is recommended only if the patient develops symptoms [12].

Another disease associated with intestinal ganglioneuromatosis is Cowden syndrome [13,14]. With an incidence of 1:200,000, CS is an autosomal dominant disorder denoted by germline mutations in PTEN, a tumor suppressor gene [15,16]. Early diagnosis of CS is essential due to a lifetime risk of breast, thyroid, and endometrial cancer as high as 85%, 35%, and 28%, respectively [16]. The National Comprehensive Cancer Network has established guidelines regarding the management of Cowden Syndrome [17]. Starting at age 18 years, women diagnosed with CS should receive education and training on breast self-exam, and undergo clinical breast exams every 6–12 months starting at 25 years or 5–10 years before the earliest diagnosis of breast cancer in the family. Similarly, annual mammography and breast MRI screening should start at 30–35 years or individualized based on earliest age of onset in the family. Women with CS should be educated on the signs and symptoms of endometrial cancer to prompt immediate investigation and possible treatment. Risk-reducing mastectomy and hysterectomy should be discussed on an individual basis. Surveillance for both men and women should begin at age 18 years or 5 years before the earliest cancer diagnosis in the family, and should include annual comprehensive physical exams with specific attention to the breasts and thyroid. Patients should also undergo a baseline thyroid ultrasound at 18 years with consideration for annual ultrasound examination thereafter. Physicians should consider performing colonoscopies starting at age 35 years and repeat every 5–10 years. If polyps are identified or the patient is symptomatic, screening should be performed more frequently. Annual dermatologic exams should also be considered, and all patients should be educated on the signs and symptoms of cancer [17].

While the incidence of intestinal ganglioneuromatosis is very low, the importance of its diagnosis is significant. Surgical resection is often required; however, the potential for a concurrent pheochromocytoma or impending malignancy can be critical to the overall management of the patient. The diagnosis of intestinal ganglioneuromatosis necessitates further work-up for the presence of associated diseases. Furthermore, progressive intestinal involvement may occur, requiring additional bowel resection, as was the case here.