Case 6-2013: A 54-Year-Old Man

with Recurrent Diarrhea

Pembimbing: Prof. dr. W.H. Sibuea, SpPD

• Dr. Michael T. Forrester (Medicine): A 54-year-old man was admitted to this hospital because of diarrhea, vomiting, and weight loss

History •abdominal cramping and

nonbloody diarrhea developed 1 day after he flew from the Northeast to Colorado for a skiing trip; the symptoms persisted for the duration of his 4-day vacation

2.5 years before

admission

• 4 days after returning home emergency department of another hospital because of persistent symptomsa stomach virus

• The next day, he saw his primary care provider ciprofloxacin was administered, without benefit

• 1 month later a gastroenterologist. Routine laboratory studies were normal. A stool specimen showed many leukocytes and no ova or parasites; a stool assay for Clostridium difficile and a stool culture were negative. A course of metronidazole was administered for 10 days, and the symptoms nearly resolved

Two years before admissionEsophagogastroduodenoscopy:• An inlet patch (i.e., an area of ectopic gastric mucosa) involving

the circumference of the cervical esophagus and extending at least 4 cm in length

• Multiple erosions of the gastric antrum• Antral gastritis• Superficial ulcerations in the duodenum and • A prominent mucosal fold in the gastric side of the

gastroesophageal junction

Pathological (biopsy of the esophagus)• squamous mucosa and gastric-type mucosa, with intestinal

metaplasia that was thought to be consistent with Barrett’s esophagus

Inlet patch

Two years before admission

Colonoscopy : several small polyps

Pathological examination (biopsy specimen of a polyp in the transverse colon):

• adenomatous changes and low-grade dysplasia• a hyperplastic rectal polyp • normal fragments of duodenal mucosa • Testing for Helicobacter pylori and giardia was negative.

Proton-pump inhibitors were prescribed.

Nine months later(15 month before admission)

• 1 day after another flight to Colorado awoke with abdominal cramps and watery diarrhea (up to one episode per hour)

• 3 days later, nausea and vomiting developed• Examination of a stool specimen at that time

revealed Blastocystis hominis, and the symptoms again resolved after treatment with metronidazole.

Four months before admission

The patient traveled to the Middle East• The day after arrivalabdominal cramping developed,

with watery, nonbloody diarrhea occurring every 1 to 2 hours during the day and occasionally awakening him at night. His discomfort increased with eating.

• On the sixth day, nausea and nonbloody, nonbilious vomiting (two to three episodes daily) occurred, in association with increased diarrhea and without fevers or diaphoresis.

• None of his 15 travel companions had symptoms.

Twelve days later• The patient returned home. His symptoms

persistedhe went to a second hospital for evaluation; intravenous fluids and metronidazole were administered, but the symptoms worsened.

• Examination of the stool for pathogens and screening for H. pylori were negative.

• During the next 3 months, anorexia developed, and the patient lost 15.9 kg.

• Approximately 2 weeks before admission, his physician prescribed trimethoprim–sulfamethoxazole, with partial improvement of diarrhea.

Eight days before admission

• In the infectious-disease clinic of this hospital.• On examination, the blood pressure was 114/86

mm Hg and the pulse was 88 beats per minute; the remainder of the physical

examination was normal• Laboratory : normal (Table 1)• Stool specimens showed no enteric pathogens,

ova, or parasites, and testing for C. difficile toxin was negative

• During the ensuing week, the patient’s symptoms worsened and included diarrhea (occurring hourly throughout the day), constant nausea, vomiting within 3 minutes after oral intake, and weakness, with orthostatic lightheadedness.

Anamnesis On admission

• No fever, chills, sweats, flushing, or headache. • His only medication was omeprazole, 20 mg daily,

which he took for symptoms of gastroesophageal reflux.

• He had no known allergies. • He drank alcohol in moderation, had smoked as a

young adult, and did not use illicit drugs. • His father was 82 years of age and had dementia• His mother was deceased and had a history of

Parkinson’s disease and heart disease, • Uncle reportedly had stomach cancer.

Examination

• The blood pressure was 133/94 mm Hg and the pulse 120 beats per minute; the temperature, respirations, and oxygen saturation were normal, as was the remainder of the examination.

• Laboratoty are shown in Table 1. • An electrocardiogram was normal. • Normal saline was infused. The patient was

admitted to this hospital.

CT + contras abdomen and pelvis

Thickening and enhancement of the proximal small-bowel walls, mild dilatation in the small bowel, a large amount of fluid in the small bowel and colon with air–fluid levels, an enlarged retroperitoneal node (1.3 cm in the short axis), calcific atherosclerosisof the aorta, and a ground-glass nodule (0.7 cm in diameter) in the lower lobe of the right lung

• Testing for human immunodeficiency virus (HIV) antibodies was negative; other test results are shown in Table 1.

• Stool studies were again unrevealing.• On the fourth day, the level of potassium in

the stool was 21.7 mmol per liter (serum level, 3.4 mmol per liter) and stool fat was 37% (reference range, 0 to 19)

Esophagogastroduodenoscopy

• Revealed erosive or exudative circumferential lesions (grade III esophagitis, according to the modified Savary–Miller classification, which consists of grades I through V, with grade V indicating the metaplasia seen in Barrett’s esophagus)

• Excessive fluid (1600 ml) in the gastric body; • A partially obstructing duodenal ulcer (30 mm in the

largest dimension) in the duodenal bulb, with an ulcer crater that was suspicious for perforation; and multiple ulcers, up to 6 mm in the largest dimension, in the second part of the duodenum.

• Pathological examination: Duodenal mucosa with ulceration, foveolar metaplasia, and hyperplasia of the Brunner’s glands, with no evidence of malignant cells.

• Gram’s staining of an aspirate of the duodenum revealed few polymorphonuclear cells and few yeast forms; no ova or parasites were seen.

• Cultures of the duodenal aspirate grew Candida albicans and three colony types of alpha-hemolytic streptococcus.

Differential considerations

• Differential considerations for duodenal ulcers include acid exposure, acid-producing tumors (the Zollinger–Ellison syndrome), or peptic ulcer disease.

• Differential considerations for solid tumors of the pancreas should always include pancreatic adenocarcinoma, metastases (most commonly from renal-cell carcinoma or melanoma, and occasionally from ovarian cancer), and neuroendocrine tumors.

Differential considerations

• Classic findings for pancreatic adenocarcinoma include ductal dilatation of the pancreas, biliary dilatation, and jaundice, and this patient had none of those.

• Therefore, the pertinent negative findings associated with this case steer us away from a diagnosis of pancreatic adenocarcinoma X

Acute diarrheal illness

• This patient’s initial episodes of diarrheal illness were typical of acute gastroenteritis, for which a definite cause is often not identified.

• Most acute diarrheal episodes (those lasting >7 days) are caused by self-limited bacterial or viral infections; more prolonged courses of acute diarrheal illness are caused by protozoans, including cryptosporidium and Giardia lamblia.

• During the patient’s second diarrheal illness, the finding of B. hominis in the stool specimen was of debatable clinical relevance. This organism is commonly found in stool samples, and the response to treatment is variable.

• Thus, his improvement after treatment suggests that he may have had a symptomatic B. hominis infection, although we cannot be certain that this was the cause of his illness.

• At this point, the main diagnostic considerations include recurrent infectious gastroenteritis or the initial presentation of inflammatory bowel disease.

• The initial endoscopic studies revealed no evidence of colitis, but the upper endoscopy revealed erosions of the gastric antrum and duodenum. Crohn’s disease should be considered, because small-bowel involvement in patients with Crohn’s disease can cause a large-volume, watery diarrheal illness.

• During the last 4 months before this patient’s hospitalization, he had an acceleration of his clinical course. Therefore, the differential diagnosis for his illness must broaden to include the causes of chronic diarrhea, which is defined as diarrheal illness lasting for more than 4 weeks

• The major causes of chronic diarrhea can be assessed by combining a patient’s history and classification of the stool (inflammatory, fatty, or watery).

• This patient had no blood in his stools and little evidence of inflammation or infection, and endoscopic evaluation 2 years before admission revealed no conclusive evidence of inflammatory bowel disease.

Celiac disease• Should be considered, given his weight loss and

diarrhea, but he did not have greasy or malodorous stools, and tests for IgA antibodies to endomysial antigen and tissue transglutaminase were negative

• Finally, examination of the patient’s duodenal-biopsy specimen did not show the villous atrophy that is the signature pathological feature of celiac disease

• His clinical picture is most notable for chronic watery stools

Chronic watery stools

Stool osmotic gap

Stool osmolality − {2 x (stool Na + stool K)}

Potassium (mmol/liter) 21,7

306 - {2 x (96+ 21,7)} = 306 – 235,4 = 70,6

Stool osmotic gap

• High osmotic gap (>125 mosm/kg) causes of osmotic diarrhea

• Low osmotic gap (<50 mosm/kg) causes of secretory diarrhea

• this patient’s calculated stool osmotic gap was in the lowintermediate range at 70, with a high level of sodium in the stool, suggesting that a secretory process is more likely than osmotic diarrhea

Endocrinopathy

• This patient was appropriately evaluated for the most common endocrinologic causes of diarrhea, including diabetes mellitus, hyperthyroidism, and adrenal insufficiency.

• Systemic mastocytosis could be a unifying diagnosis for peptic ulcer disease and diarrhea; however, the absence of a history of urticaria and the absence of findings of mast-cell infiltration on examination of the previous esophageal-biopsy specimens make this diagnosis unlikely

Peptide-Secreting Tumors

• The major peptide-secreting tumors to be considered in this patient are carcinoid tumor, vasoactive intestinal peptide–producing tumor (VIPoma), and gastrinoma. The absence of flushing makes carcinoid tumor less likely. VIPoma is classically associated with profound hypokalemia and hypochlorhydria, which were not present

Gastrinoma

• On the patient’s second upper endoscopy, the finding of a large duodenal ulcer with a crater, as well as multiple smaller ulcers, raises concern for gastric-acid hypersecretion. This patient had a negative test for H. pylori antibody and did not use nonsteroidal antiinflammatory drugs, ruling out the two most common causes of peptic ulcer disease. Ulcers developed despite his regular use of a proton-pump inhibitor, which is an unusual finding that deserves further investigation

Gastrinoma

• Gastrinoma, a rare tumor of the pancreas and duodenum, causes ectopic hypersecretion of gastrin and results in the hypersecretion of gastric acid, leading to severe peptic ulcer disease; this complex of findings is known as the Zollinger– Ellison syndrome and is often accompanied by esophageal reflux disease and diarrhea

• On this patient’s first upper endoscopy (2 years before admission), mention was made of a prominent gastric fold, an unusual finding.

• In one series, a prominent gastric fold was found in more than 90% of patients with the Zollinger–Ellison syndrome.

• The factors that contribute to gastrinoma-associated diarrhea are a high volume of gastric acid; inactivation of pancreatic digestive enzymes by gastric acid, causing steatorrhea; and inhibition of sodium and water reabsorption by the small intestine, causing a secretory diarrhea

Gastrinoma

• Slightly more common in men than in women, and the age at onset is generally between 41 and 53 years of age.

• On average, the diagnosis is made 5 years after the onset of symptoms. This patient was 51 years of age at the onset of his symptoms, which is typical

• Twenty to 25% of patients with gastrinoma have the multiple endocrine neoplasia type 1 (MEN-1) syndrome. Almost all patients with MEN-1 have primary hyperparathyroidism.

• Since this patient’s calcium levels remained normal, even when he was in a volume-depleted state, it is unlikely that he had hyperparathyroidism

• Testing for gastrinoma starts with measurement of a fasting serum gastrin level. The gastrin level is elevated in virtually all patients with the Zollinger–Ellison syndrome; therefore, a normal level essentially rules out this condition. However, our measurements could be confounded by the patient’s recent use of proton-pump inhibitors, which can raise the fasting gastrin levels markedly

• A gastrin level that increases by more than 120 pg per milliliter in response to secretin is diagnostic of a gastrinoma

• CLINICAL DIAGNOSIS: Neuroendocrine tumor of the pancreas

• DR. LEIGH H. SIMMONS’s DIAGNOSIS:Sporadic (non–multiple endocrine neoplasia type 1) Zollinger–Ellison syndrome (gastrinoma)

Pathological discussion

The specimen consisted of a segment of distal stomach, 6.5 cm in length, attached to a segment of duodenum, 25 cm in length, surrounding the head of the pancreas, which contained a mass that measured 6.2 cm in diameter. An ulcer (2 cm in diameter) without heaped-up edges was present in the proximal duodenum.

The pancreatic mass was circumscribed and was composed of firm, white tissue and darker, more hemorrhagic tissue adjacent to the normal-appearing yellow-tan pancreas

Microscopically, nests of tumor cells were separated by fibrous tissue. The tumor cells were relatively uniform and round, with pink cytoplasm and central round nuclei with the fine “salt and pepper” chromatin that is characteristic of neuroendocrine cells

Immunohistochemical staining of the tumor cells was positive for gastrin

• The World Health Organization distinguishes among three grades of neuroendocrine tumors:

• Grades 1 and 2 consist of well-differentiated tumors, and grade 3 consists of poorly differentiated tumors, including small-cell carcinoma. Grade 1 and grade 2 are separated by mitoses and the proliferation index, assessed with Ki67 immunostaining.

• The tumor in this case had fewer than two mitoses per 10 high-power fields, had a Ki67 index of less than 3%, and expressed the neuroendocrine markers chromogranin and synaptophysin, as well as gastrin. Thus, the tumor is classified as a well-differentiated pancreatic neuroendocrine neoplasm (gastrinoma), grade 1.

• Lymphatic invasion was present, the margins were negative, and 4 out of 31 lymph nodes were positive. On the basis of size and the involvement of peripancreatic tissue, as well as the number of positive lymph nodes, the stage was determined to be pT3N1Mx

Final Diagnosis

• Serum gastrin levels measured at the time of surgery were markedly elevated, at 1329 pg per milliliter.

• After surgery, the gastrin levels have remained normal.

• Therefore, the final diagnosis in this case is the Zollinger–Ellison syndrome, caused by pancreatic gastrin-secreting neuroendocrine neoplasm (gastrinoma).

Follow up

• Dr. Lawrence S. Blaszkowsky (Hematology–Oncology): I was asked to see the patient to assess the need for adjuvant therapy because of a posterior (retroperitoneal) margin of less than 1 mm.

• There is no established role for adjuvant therapy in this disease. We consider adjuvant therapy in cases of a close or positive surgical margin, but there is a paucity of data to support such therapy.

• Our standard approach is to offer radiotherapy in combination with chemotherapy to serve as a radiation sensitizer.

• In this patient, we were unable to initiate adjuvant therapy for about 3 months because a fluid collection developed that required percutaneous drainage.

• Approximately 3 weeks after the completion of chemoradiation, the patient presented to another hospital with severe abdominal pain, and imaging studies suggested a perforated viscus. He was transferred to this hospital, and the surgeon repaired the ulcer and removed the residual lymph node that had been seen on postoperative imaging.

• Twenty months after chemoradiation, the patient is doing well. The gastrin level is normal, and he has no evidence of recurrent disease.

Prognosis

• The estimated 5-year survival rate among patients with regional disease is more than 50%.

• Recurrence is possible, but neuroendocrine tumors tend to be relatively indolent as compared with adenocarcinoma.

• Agents such as sunitinib and everolimus may be options for this patient if the disease recurs

Anatomical diagnosis

Gastrinoma

Thank You