CHRISTINA L. MASTER
HISTORY OF PRESENT ILLNESS
The patient is a 2-year-old boy who was well until 5 months prior to admission when he developed intermittent watery diarrhea. He has had more than three large watery stools per day, sometimes up to 10 such stools per day. As an outpatient, he was seen and examined. A stool culture was negative as were tests for Clostridium difficile and ova and parasites. Other blood tests sent at that time were also normal according to his mother. Since then, he has been seen once in an emergency department where he was treated for an intestinal parasite without any improvement in his symptoms. He had been otherwise well appearing during these last 5 months until the day prior to presentation to the hospital when he had significantly decreased oral intake, has had decreased activity, and has been acting cranky. On the day of admission to the hospital he had three episodes on nonbloody and nonbilious emesis. He also has developed a tactile temperature and is refusing to walk. He has not had any rash or weight loss according to his mother. She is unsure about his urine output.
The boy is a former premature infant born at 33 weeks gestation and did not require endotracheal intubation. Surgical procedures included patent ductus arteriosus ligation, inguinal hernia repair, and removal of a vocal cord cyst. He was hospitalized 6 months ago for pneumonia and has had recurrent episodes of otitis media (6 episodes). His only medication is a multivitamin. His family history is significant only for type 2 diabetes mellitus and asthma.
T 38.5°C; RR 24/min; HR 117 bpm; BP 108/54 mmHg
Weight 25th percentile
The boy’s examination revealed an ill-appearing but responsive toddler. His head and neck examinations were significant only for tacky mucous membranes. His cardiac and respiratory examinations were normal. His abdomen was soft and nontender without any organomegaly. His rectal examination was normal and the stool was heme negative. His extremity examination was unremarkable and his neurologic examination was nonfocal, but he continued to refuse to walk.
A complete blood count revealed a WBC count of 9600 cells/mm3 (66% segmented neutrophils; 24% lymphocytes; 9% monocytes; 1% eosinophils), a hemoglobin of 15.1 g/dL, and a platelet count of 291 000 cells/mm3. Serum electrolytes were significant for potassium 2.1 mmol/L, bicarbonate 11 mmol/L, and alkaline phosphatase was 214 U/L. Cerebrospinal fluid (CSF) analysis revealed no WBCs/mm3 and 4 RBCs/mm3. CSF protein and glucose were normal. His urinalysis was significant for moderate blood with 5-10 RBCs/hpf and 0-2 WBCs/hpf.
COURSE OF ILLNESS
The patient took nothing by mouth while in the hospital, but continued to make more than 2 L per day of diarrhea for the next 3 days. Despite intravenous fluid repletion, his serum bicarbonate never rose above 18 mmol/L. Repeat stool cultures for bacteria and viruses, stool examination for ova and parasites, and assays for C. difficile toxins A and B were all negative. Stool antigen testing for Giardia and Cryptosporidium were also negative. An abdominal radiograph (Figure 17-6) and CT (Figure 17-7) directed further testing.
FIGURE 17-6. Abdominal radiograph.
FIGURE 17-7. Abdominal CT.
DISCUSSION CASE 17-6
The chronic nature of his diarrhea for the last 5 months makes acute infectious diarrhea, due to either bacterial or viral causes, highly unlikely. It is possible that the toddler has lactase or other disaccharidase deficiency secondary to an episode of infectious gastroenteritis, but other entities must be considered. Infectious enteritis caused by C. difficile and ova and parasites must be considered, although there is no history of antibiotic use, bloody diarrhea, foreign travel, or use of untreated water sources. He is too ill appearing to consider the toddler’s diarrhea as a cause. Other entities that cause chronic diarrhea such as inflammatory bowel disease or celiac disease are considerations, but there is a key finding during the patient’s hospital stay that quickly directs us down another path. While in the hospital, the patient took nothing by mouth but continued to produce profuse voluminous watery diarrhea which indicated the presence of secretory, rather than osmotic, diarrhea. In this differential diagnosis, the list is rather brief, including rare congenital and paraneoplastic conditions. Congenital defects in chloride or sodium transport are unlikely to present in a 2-year old in this fashion. Infectious causes of secretory diarrhea include small bowel overgrowth or infection with immunoadherent Escherichia coli stimulating gastrointestinal secretions. Any cause of villous atrophy, whether congenital, autoimmune, or secondary to immune deficiency, such as severe combined immune deficiency or human immunodeficiency virus (HIV) infection may also present with chronic diarrhea. Neuroblastoma, or other tumors of neural crest origin, such as ganglioneuroma, may secrete vasoactive intestinal peptide, resulting in secretory diarrhea.
An abdominal radiograph showed calcifications above the left kidney (Figure 17-6) and subsequent computed tomography revealed a large left adrenal mass (Figure 17-7). Surgery was performed and the mass was completely resected and was identified as a ganglioneuroblastoma on pathology. The vasoactive intestinal peptide (VIP) level returned at 195 (normal <70).
These findings were consistent with the diagnosis of VIP-secreting ganglioneuroblastoma causing secretory diarrhea. Immediately following surgery, his diarrhea resolved and a repeat VIP level was normal.
INCIDENCE AND ETIOLOGY
Most VIP-secreting tumors in childhood are neurogenic in origin, as opposed to those in adults, most of which are of pancreatic islet cell origin. Pediatric patients usually present during the first 10 years of life. Most pediatric tumors are adrenal or retroperitoneal in location and ganglioneuromas or ganglioneuroblastomas are common.
Generally speaking, pediatric patients will present as this child did, with profuse, watery, secretory diarrhea, and not with a palpable mass. The biochemical profile is that of hypokalemia and achlorhydria due to the effect of VIP on the gastrointestinal tract to promote secretion of water and electrolytes and inhibiting gastric acid secretion. Calcifications may also be noted incidentally on X-ray and thus prompt further investigation.
Clinical observation. The observation of continued, intractable watery diarrhea while the patient takes nothing by mouth is key to the ultimate diagnosis. Whether this is accomplished by obtaining a very thorough history or by observation while in the hospital, this piece of information is vital to making the ultimate diagnosis.
Radiographs. Radiographs may localize calcifications and often provide the first indication of the presence of such a tumor as an incidental finding.
Computed tomography. Computed tomography will more accurately delineate the location of the tumor, which is usually retroperitoneal or adrenal. Occasionally, tumors may be found along the sympathetic chain in the thoracic region.
Peptide panel. Elevated plasma VIP levels are diagnostic. Other peptides that are tested include gastrin, somatostatin, calcitonin, and serotonin. These peptides are elaborated by tumors not commonly found in the pediatric population (gastrinoma, carcinoid syndrome, medullary thyroid carcinoma, mastocytosis, and villous adenoma of the rectosigmoid colon).
Surgical removal. Complete surgical excision provides a pathologic specimen for further identification and characterization of the tumor and is also therapeutic, especially with regard to the secretory diarrhea.
Complete surgical excision is necessary and sufficient to cure the secretory diarrhea. Somatostatin analogs have been shown to decrease diarrhea due to the inhibitory effect on gastrointestinal secretions, but surgery remains the definitive treatment. Subsequent chemotherapy is then determined based on the type of tumor and the tissue pathology as well as other information, such as the presence of molecular amplification of oncogenes.
1. Zella GC, Israel EJ. Chronic diarrhea in children. Pediatr Rev. 2012;33(5):207-218.
2. Husain K, Thomas E, Demerdash Z, Alexander S. Mediastinal ganglioneuroblastoma-secreting vasoactive intestinal peptide causing secretory diarrhoea. Arab J Gastroenterol. 2011;12(2):106-108.
3. Bourdeaut F, de Carli E, Timsit S, et al; Neuroblastoma Committee of the Société Française des Cancers et Leucémies de l’Enfant et de l’Adolescent. VIP hypersecretion as primary or secondary syndrome in neuroblastoma: a retrospective study by the Societe Francaise des Cacers de l’Enfant (SCFE). Pediatr Blood Cancer. 2009;52(5):585-590.
4. Keating JP. Chronic diarrhea. Pediatr Rev. 2005;26(1):5-14.
5. Nikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepatogastroenterology. 2005;52(64): 1259-1265.
6. Rodriguez M, Regalado J, Zaleski C, Thomas C, Tamer A. Chronic watery diarrhea in a 22-month-old girl. J Pediatr. 2000;136:262-265.
7. Murphy M, Sibal A, Mann JR. Persistent diarrhoea and occult vipomas in children. BMJ. 2000;320: 1524-1526.