Megacolon as the Presenting Feature in Pheochromocytoma

Ann T. Sweeney, Alan O. Malabanan, Michael A. Blake, Antonio de las Morenas, Riad Cachecho and James C. Melby

Departments of Medicine, Section of Endocrinology Diabetes and Nutrition (A.T.S., A.O.M., J.C.M.), Radiology (M.A.B.), Pathology (A.d.l.M.), and Surgery (R.C.), Boston University Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Dr. James C. Melby, Endocrine Hypertension Unit, Department of Medicine and Physiology, Boston University School of Medicine, Evans Building, Room 232, Boston, Massachusetts 02118. E-mail: James.Melby{at}bmc.org


    Introduction
 Top
 Introduction
 Case Report
 Discussion
 References
 
Pheochromocytoma is a rare catecholamine-secreting tumor that may present in a protean manner. Gastrointestinal manifestations of pheochromocytoma are common and include nausea, vomiting, and abdominal pain, but megacolon, in the absence of the multiple endocrine neoplasia syndromes (MEN 2A and 2B), has rarely been described. In this report megacolon was the presenting feature of the patient’s pheochromocytoma. We discuss the role of catecholamines in the pathogenesis of a megacolon and emphasize the importance of recognizing this rare, but often lethal, combination.


    Case Report
 Top
 Introduction
 Case Report
 Discussion
 References
 
A 38-yr-old female with a history of hypertension, migraines, and constipation presented to our emergency room complaining of severe abdominal pain and constipation. She had a 4-yr history of constipation, with an average of two bowel movements per week. The pain began 10 days before admission, was diffuse, and progressively worsened. She had not had a bowel movement in 10 days. She described increasing abdominal girth and nausea but no vomiting. Her medications included hydrochlorothiazide (25 mg, orally, daily), enalapril (10 mg, orally, daily), and over the counter laxatives as needed. Her family history was noncontributory.

Physical examination revealed a thin female writhing in pain. Her blood pressure was 182/155 mm Hg, heart rate was 116 beats/min, respirations were shallow at 22/min, and temperature was 36.5 C. Her fundi were without hemorrhages or exudates, and disk margins were sharp. Her cardiac exam revealed a hyperdynamic precordium, normal first and second heart sounds, and a II/VI systolic flow murmur at the left sternal border. Examination was otherwise significant for a distended abdomen with decreased bowel sounds and diffuse tenderness. Initial laboratory studies revealed a white blood cell count of 19,000 mm-3 (SI; 19 x 109/L; normal range conventional; SI; 4:000–11.,000 mm-3; 4.0–11 x 109/L) with a left shift, hemoglobin of 14 g/dL (140 g/L; 13.5–18.0 g/dL; 135–180 g/L), platelet count of 276 x 103/mm3 (276 x 109/L; 150–400 x 103/mm3; 150–400 x 109/L), and normal electrolytes. Her abdominal radiograph revealed large dilated loops of colon, a large amount of stool in the cecum, and no gas within the rectum (Fig. 1Go). The cecum was dilated to 10 cm. A diagnosis of large bowel obstruction secondary to fecal impaction was made. Attempt at manual disimpaction was unsuccessful.



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Figure 1. Plain film of the abdomen shows marked gaseous distention of the colon.

 
After admission, the patient was treated with naso-gastric tube decompression, pain control, and multiple enemas. Colonoscopy revealed normal mucosa to 65 cm without any masses. Further examination was impeded by impacted stool. Aggressive therapy with cathartics, external enemas, and further nasogastric tube decompression was continued. A gastrograffin enema revealed an obstructing fecal bolus within the distal descending colon. She remained significantly hypertensive throughout this period with systolic blood pressures ranging from 160–220 mm Hg, and diastolic pressures ranging from 90–120 mm Hg. She was started on methyldopa, which was titrated to 750 mg, iv, every 6 h.

After 5 days in the hospital, her clinical situation worsened as she developed increasing abdominal pain and distention. Abdominal plain film demonstrated cecal dilatation to 13 cm. Urgent surgical exploration revealed a megacolon with volvulus. A subtotal colectomy with primary ileorectal anastamosis was performed. She was significantly hypertensive during surgery and required multiple doses of iv labetolol for blood pressure control. The patient did well postoperatively until day 6, when she redeveloped acute abdominal pain with peritoneal signs. A computed tomographic scan of the abdomen was performed and revealed a small amount of fluid in the pelvis, persistent pneumoperitoneum, and a 6 x 7-cm adrenal mass (Fig. 2Go).



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Figure 2. Axial abdominal computed tomographic scan displays a well circumscribed mass (short arrow) of heterogeneous soft tissue attenuation in the right suprarenal area. Oral contrast is present in the stomach (long arrow).

 
Endocrine consultation revealed that her migraines and hypertension began simultaneously 5 yr previously. She described experiencing severe headaches accompanied by palpitations, skin warmth, and a sensation that her blood pressure was rising. Initially these spells occurred once a month, but had progressively increased to a few times per week. The constipation also started around the same time and had become progressively worse despite stool softeners and laxatives. Examination was remarkable only for cachexia, tachycardia, and mild systolic hypertension (140/79 mm Hg). She did not display marfanoid features or have mucosal neuromas. An abdominal magnetic resonance imaging scan demonstrated a 7 x 7-cm heterogeneous mass in the right adrenal gland that appeared hyperintense on T2 weighted images consistent with a pheochromocytoma. Therapy with phenoxybenzamine (10 mg, orally, twice daily) dramatically lowered the patient’s blood pressure to 90/60 mm Hg. Despite volume repletion, she remained significantly tachycardic, with a heart rate of 120 beats/min or more. Atenolol (25 mg/day, orally) was added and reduced her heart rate to approximately 90 beats/min.

Her 24-h urine results confirmed the diagnosis of pheochromocytoma. The 24-h urine collection revealed: norepinephrine, 883 µg (5,219 nmol; normal, 11–86 µg/day; 65–508 nmol/day); epinephrine, 675 µg (3,685 nmol; 0–15 µg/day; 0–81.9 nmol/day); dopamine, 441 µg (2,879 pmol; 100–400 µg/day; 653–2,612 pmol/day); total unconjugated catecholamines, 1,999 µg (11,816 nmol; <540 µg/day; <3,191 nmol/day); and total metanephrines, 17.1 mg (93.33 µmol; <1.3 mg/day; <7.13 µmol/day). Other laboratory results included serum calcitonin, 2 pg/mL (0.58 pmol/L; <5 pg/mL; <1.45 pmol/L); intact PTH, 34 pg/mL (34 ng/L; 10–65 pg/mL; 10–65. ng/L); and calcium, 10.0 mg/dL (2.50 mmol/L; 8.4–10.2 mg/dL; 2.1–2.55 mmol/L).

After adequate {alpha} and ß blockade, she underwent surgical resection of her right adrenal gland. Intraoperatively her blood pressure was labile during manipulation of the tumor, and she required large doses of iv nitroprusside and esmolol. A 200-g, well circumscribed mass was removed without complications. Postoperatively she was transiently hypotensive and required a large amount of fluid as well as temporary support with vasopressors.

Pathology

Gross examination revealed a 200-g, 4 x 7 x 8-cm encapsulated pheochromocytoma. The cut surface was reddish brown with yellow areas of necrosis. Microscopically, the tumor cells were arranged in circular clusters separated by endothelium lined spaces; this characteristic pattern for pheochromocytoma is termed zellballen (Fig. 3Go).



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Figure 3. Microscopic view (hematoxylin-eosin stain; magnification, x100) of pheochromocytoma showing typical zellballen pattern with nests of cells separated by thin vascular stroma.

 
Histological examination of the colectomy specimen revealed focal mucosal coagulation necrosis, submucosal hemorrhage, and acute and chronic inflammatory infiltrate. No abnormality was noted in the myenteric plexus, and there was no evidence of ganglioneuromatosis.

Follow-up

She was last seen 10 months after surgery; she remains normotensive without medication and has experienced no further spells. Her constipation has completely resolved. Repeat 24-h urine for total catecholamines, metanephrines, and vanillylmandelic acid returned within normal limits. The serum chromogranin A level was within the normal range, and screening for mutations in the RET protooncogene was negative. No mutations were detected in exons 10 (codons 609, 611, 618, and 620), 11 (codon 634), 13, 14, or 16 (codon 918) of the RET protooncogene.


    Discussion
 Top
 Introduction
 Case Report
 Discussion
 References
 
Pheochromocytoma classically presents with hypertension in association with palpitations, headaches, and diaphoresis. This constellation of symptoms is said to be 91% sensitive and 94% specific for the diagnosis of pheochromocytoma (1). Our patient displayed all of these symptoms; however, her initial presentation with an ileus and megacolon may not immediately bring to mind the diagnosis of pheochromocytoma. The differential diagnosis for megacolon includes Hirschprung’s, Chaga’s, and Parkinson’s diseases; diabetic neuropathy; myotonic dystrophy; hypothyroidism; amyloidosis; and pheochromocytoma. A few standard internal medicine textbooks do not even list pheochromocytoma in the differential diagnosis of megacolon (2, 3).

The typical gastrointestinal manifestations of pheochromocytoma include nausea, vomiting, and abdominal pain. Constipation has been reported in 5–13% of cases in a larger series (4). Megacolon and pheochromocytoma may occur together in MEN 2A and MEN 2B. Hirschprung’s disease, or congenital aganglionic colon, has been reported in association with both MEN 2A and 2B syndromes (5). In MEN 2A, at least six germline mutations (involving codons 609, 611, 618, and 620) of the RET protooncogene located on chromosome 10 (10q11.2) have been identified (6). Evidence has demonstrated that Hirschsprung’s disease is also linked to the RET protooncogene (7). Patients with MEN 2B and neurofibromatosis may also develop megacolon (8). Diffuse ganglioneuromatosis of the colon in MEN 2B is thought to cause a dysmotility syndrome that may precipitate megacolon (9). A germline missense mutation in the tyrosine kinase domain of the RET protooncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B (10). Our patient’s phenotypic features, colon pathology, and genetic testing clearly were not consistent with Hirschprung’s disease, MEN 2A, or MEN 2B.

Sustained high catecholamine levels secreted by a high tumor burden may explain the mechanism by which constipation, paralytic ileus, and megacolon occur in association with pheochromocytoma. The effects of catecholamines on intestinal smooth muscle and the splanchnic circulation are well known (11). Stimulation of {alpha} receptors causes hyperpolarization and relaxation of intestinal smooth muscle ({alpha}1), constriction of intestinal vascular smooth muscle ({alpha}1 and {alpha}2), and contraction of ileocolic sphincters ({alpha}2). Stimulation of ß2 receptors causes arteriolar dilatation and intestinal smooth muscle relaxation. Therefore, high levels of circulating catecholamines will result in a decrease in intestinal peristalsis, motility, and tone. Clinically this may manifest initially as intermittent constipation, but when catecholamine levels become persistently elevated, they may precipitate an ileus or perhaps a megacolon. Cruz and Colwell reported a series of seven patients who developed ileus with large pheochromocytomas (>70 g) and catecholamine levels at least twice normal (>1,000 µg/day; 5,910 nmol/day) (12). As shown in Table 1Go, only the largest pheochromocytomas (>200 g) with circulating catecholamine levels approaching 4 times normal (>1,999 µg/day; 11,814 nmol/day) developed megacolon.


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Table 1. Review of the literature: cases of megacolon, paralytic ileus, or pseudoobstruction in association with pheochromocytoma

 
Factors other than serum catecholamines may play a role in the development of ileus or megacolon. There is evidence that opioid peptides may be synthesized and secreted by pheochromocytomas (13). As narcotic analgesics are known to induce constipation and megacolon, perhaps a noncatecholamine product, such as an opioid compound, may have played a contributory role in the pathogenesis of megacolon.

Some patients with pheochromocytoma and pseudo-obstruction, however, have been reported to have a dramatic relief after the iv administration of phentolamine, an {alpha}-adrenergic blocker. This suggests that {alpha}-adrenergic activation by high circulating catecholamine levels is largely responsible for pseudo-obstruction observed in patients with pheochromocytoma (14, 15).

The effects of catecholamines on the intestine were initially described by Blacket et al. in 1950 (16). They continuously infused noradrenaline to four rabbits over 4 days. This resulted in the premature death of one rabbit that at autopsy was found to have enormous dilatation of the large gut. Two of the other rabbits subsequently became ill and on postmortem exam also exhibited gross dilatation of the terminal large gut.

Review of the literature reveals that the presence of megacolon in association with pheochromocytoma carries a grave prognosis (see Table 1Go). Our patient was extremely fortunate to have survived a total colectomy before the discovery of her pheochromocytoma. Perhaps the diagnosis could have been made sooner had the association of megacolon and pheochromocytoma been recognized.

Conclusion

In summary, we describe a patient with a history of hypertension, migraine headaches, and constipation presenting with severe abdominal pain and megacolon who ultimately was found to have a pheochromocytoma. High circulating catecholamine levels secreted by the large tumor undoubtedly precipitated the megacolon. We conclude that the diagnosis of pheochromocytoma should be considered in any patient who presents with megacolon, pseudo-obstruction, and features of catecholamine excess.

Received January 20, 2000.

Revised July 10, 2000.

Accepted July 18, 2000.


    References
 Top
 Introduction
 Case Report
 Discussion
 References
 

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