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Home , Gastrinoma, Stool osmotic gap

T h e new england journal o f medicine

case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

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

Leigh H. Simmons, M.D., Alexander R. Guimaraes, M.D., and Lawrence R. Zukerberg, M.D.

PRESENTATION OF CASE

Dr. Michael T. Forrester (Medicine): A 54-year-old man was admitted to this hospital From the Departments of Medicine because of diarrhea, , and weight loss. (L.H.S.), Radiology (A.R.G.), and Pathol- ogy (L.R.Z.), Massachusetts General Hos- The patient was well until approximately 2.5 years before admission, when pital; and the Departments of Medicine abdominal cramping and nonbloody diarrhea developed 1 day after he flew from (L.H.S.), Radiology (A.R.G.), and Pathol- the Northeast to Colorado for a skiing trip; the symptoms persisted for the dura- ogy (L.R.Z.), Harvard Medical School — both in Boston. tion of his 4-day vacation. Four days after returning home, he went to the emer- gency department of another hospital because of persistent symptoms, where he was N Engl J Med 2013;368:757-65. DOI: 10.1056/NEJMcpc1208149 told he had a stomach virus. The next day, he saw his primary care provider, and Copyright © 2013 Massachusetts Medical Society. ciprofloxacin was administered, without benefit. One month later, he saw a gas- troenterologist. 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 this admission, esophagogastroduodenoscopy reportedly re- vealed an inlet patch (i.e., an area of ectopic gastric mucosa) involving the circum- ference of the cervical and extending at least 4 cm in length, multiple erosions of the gastric antrum, antral , superficial ulcerations in the duo- denum, and a prominent mucosal fold in the gastric side of the gastroesophageal junction. A colonoscopy showed several small polyps. Pathological examination of the biopsy specimens of the proximal portion of the esophagus reportedly showed squamous mucosa and gastric-type mucosa, with intestinal metaplasia that was thought to be consistent with Barrett’s esophagus. Pathological examination of a biopsy specimen of a in the transverse colon revealed adenomatous changes and low-grade dysplasia; a hyperplastic rectal polyp and normal fragments of duo- denal mucosa were also seen. Testing for Helicobacter pylori and giardia was nega- tive. Proton-pump inhibitors were prescribed. Nine months later, 1 day after another flight to Colorado, the patient again awoke with abdominal cramps and watery diarrhea (up to one episode per hour); 3 days later, and vomiting developed. Examination of a stool specimen at that time revealed Blastocystis hominis, and the symptoms again resolved after treat- ment with metronidazole.

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Four months before admission, the patient industry, and was monogamous with his girl- traveled to the Middle East. While traveling, he friend. He drank alcohol in moderation, had stayed in hotels and drank only bottled water. smoked as a young adult, and did not use illicit The day after arrival, abdominal cramping devel- drugs. He had had no exposures to sick persons oped, with watery, nonbloody diarrhea occurring or animals and had no history of ingestion of every 1 to 2 hours during the day and occasion- unpasteurized milk products or raw meats. He had ally awakening him at night. His discomfort traveled annually to the Caribbean for 14 years, increased with eating. On the sixth day, nausea most recently 8 years before admission. His fa- and nonbloody, nonbilious vomiting (two to three ther was 82 years of age and had dementia, his episodes daily) occurred, in association with in- mother was deceased and had a history of Par- creased diarrhea and without fevers or diaphore- kinson’s disease and heart disease, and an uncle sis. None of his 15 travel companions had symp- reportedly had stomach . toms. Twelve days later, the patient returned On examination, the blood pressure was home. His symptoms persisted, and 3 weeks 133/94 mm Hg and the pulse 120 beats per min- after their onset, he went to a second hospital ute; the temperature, respirations, and oxygen for evaluation; intravenous fluids and metroni- saturation while the patient was breathing ambi- dazole were administered, but the symptoms ent air were normal, as was the remainder of the worsened. Examination of the stool for pathogens examination. The platelet count, activated partial- and screening for H. pylori were negative. During thromboplastin time, and serum levels of calci- the next 3 months, anorexia developed, and the um, phosphorus, , and prealbumin patient lost 15.9 kg. Approximately 2 weeks before were normal, as were the results of liver-function admission, his physician prescribed trimethoprim– tests; other test results are shown in Table 1. An sulfamethoxazole, with partial improvement of electrocardiogram was normal. Normal saline diarrhea. was infused. The patient was admitted to this Eight days before admission, the patient was hospital. seen in the infectious-disease clinic of this hos- Computed tomography (CT) of the abdomen pital. On examination, the blood pressure was and pelvis after the oral and intravenous admin- 114/86 mm Hg and the pulse was 88 beats per istration of contrast material showed thickening minute; the remainder of the physical examina- and enhancement of the proximal small-bowel tion was normal. The platelet count, erythrocyte walls, mild dilatation in the small bowel, a large sedimentation rate, red-cell indexes, and serum amount of fluid in the small bowel and colon levels of glucose, urea nitrogen, calcium, vita- with air–fluid levels, an enlarged retroperitoneal min B12, C-reactive protein, cortisol, thyrotro- node (1.3 cm in the short axis), calcific athero- pin, amylase, and lipase were normal, as were sclerosis of the aorta, and a ground-glass nodule the results of liver-function tests. Testing for IgA (0.7 cm in diameter) in the lower lobe of the antibodies to gliadin, endomysial antigen, and right lung. , prochlorperazine, and tissue transglutaminase was negative; other test ondansetron hydrochloride were administered, results are shown in Table 1. Stool specimens and additional crystalloid solution was infused showed no enteric pathogens, ova, or parasites, intravenously. Urinalysis revealed 1+ ketones and and testing for C. difficile toxin was negative. albumin and was otherwise normal. During the During the ensuing week, the patient’s symptoms next 2 days, levels of erythropoietin and folate worsened and included diarrhea (occurring hour- were found to be normal, and testing for human ly throughout the day), constant nausea, vomiting immunodeficiency virus (HIV) antibodies was within 3 minutes after oral intake, and weak- negative; other test results are shown in Table 1. ness, with orthostatic lightheadedness. He came Stool studies were again unrevealing. to the emergency department of this hospital. On the fourth day, the level of potassium in The patient reported no fever, chills, sweats, the stool was 21.7 mmol per liter (serum level, flushing, or headache. His only medication was 3.4 mmol per liter) and stool fat was 37% (refer- omeprazole, 20 mg daily, which he took for ence range, 0 to 19). Esophagogastroduodenos- symptoms of gastroesophageal reflux. He had no copy revealed erosive or exudative circumferen- known allergies. He was of Ashkenazi (Eastern tial lesions (grade III , according to European) Jewish ancestry, worked in a service the modified Savary–Miller classification, which

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Table 1. Laboratory Data.*

8 Days before, 2nd and 3rd Variable Reference Range, Adults† Outpatient Clinic On Admission Hospital Days Blood Hematocrit (%) 41.0–53.0 (men) 54.6 54 in emergency department; 44.9 49.6 after administration of intra­venous fluids Hemoglobin (g/dl) 13.5–17.5 (men) 19.1 17.9 16.0 White-cell count (per mm3) 4500–11,000 9800 16,600 17,300 Differential count (%) Neutrophils 40–70 71 76 79 Lymphocytes 22–44 16 17 12 Monocytes 4–11 10 5 7 Eosinophils 0–8 2 1 1 Basophils 0–3 1 1 1 Reticulocytes (%) 0.5–2.5 1.6 Prothrombin time (sec) 11.0–13.7 14.2 International normalized ratio for 1.2 prothrombin time Sodium (mmol/liter) 135–145 139 133 137 Potassium (mmol/liter) 3.4–4.8 3.3 3.6 3.5 Chloride (mmol/liter) 100–108 91 92 98 Carbon dioxide (mmol/liter) 23.0–31.9 26.2 30.3 29.8 (mmol/liter) 3–15 22 11 9 Creatinine (mg/dl) 0.60–1.50 1.64 1.04 1.04 Estimated glomerular filtration rate ≥60 47 >60 >60 (ml/min/1.73 m2) Glucose (mg/dl) 70–110 87 120 122 Protein (g/dl) Total 6.0–8.3 8.4 6.9 Albumin 3.3–5.0 5.2 4.2 Globulin 2.6–4.1 3.2 2.7 Osmolality (mOsm/kg of water) 280–296 283 Immunoglobulins (mg/dl) IgA 69–309 140 IgG 614–1295 425 IgM 53–334 49 Urine Sodium (mmol/liter) Not defined 102 Creatinine (mg/ml) Not defined 1.91 Stool Sodium (mmol/liter) Not defined 96 Chloride (mmol/liter) Not defined 67 Osmolality (mOsm/kg of water) Not defined 306

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the value for blood creatinine to micromoles per liter, multiply by 88.4. † Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.

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the largest dimension) in the duodenal bulb, with A an crater that was suspicious for perfora- tion; and multiple , up to 6 mm in the largest dimension, in the second part of the . Pathological examination of biopsy specimens of the edges of the partially obstruct- ing duodenal ulcer showed duodenal mucosa with ulceration, foveolar metaplasia, and hyper- plasia of the Brunner’s , with no evidence of malignant cells. Gram’s staining of an aspirate of the duodenum revealed few polymorphonu- clear cells and few yeast forms; no ova or para- sites were seen. Cultures of the duodenal aspirate grew Candida albicans and three colony types of alpha-hemolytic streptococcus. Diagnostic procedures were performed.

DIFFERENTIAL DIAGNOSIS

Dr. Leigh H. Simmons: May we review the imaging studies? Dr. Alexander R. Guimaraes: An axial and coronal reformatted image from a contrast-enhanced CT B examination reveals a fluid-filled, distended stomach with thickened gastric rugae (Fig. 1A). This pattern is noted in the duodenum and jeju- num as well, where there are thickened loops of small bowel with mild dilatation as compared with other normal loops of small bowel. The dif- ferential considerations for this finding include ischemia, vasculitis, infectious and inflammatory enteritides, ingestion (particularly acidic materi- als), hemorrhage, and trauma. Ulceration is noted within the duodenal bulb. The fluid distention of the small bowel combined Figure 1. Abdominal Imaging. with the contrast enhancement of the bowel A coronal reformatted image from a contrast-enhanced makes this finding suggestive of a mass. On the CT scan of the abdomen and pelvis (Panel A) shows mul- axial image, a mass is noted in the uncinate pro- tiple thickened loops of small bowel (small arrowheads), cess and head of the (Fig. 1B). The mass thickening of the gastric rugae (large arrowhead), and an ulceration of the first portion of the duodenum (arrow). has homogeneous enhancement. Pertinent nega- An axial image from a contrast-enhanced CT examination tive findings include an absence of pancreatic of the abdomen and pelvis (Panel B) shows loops of atrophy, pancreatic ductal dilatation, and intra- thickened proximal small bowel with thickened valvulae hepatic ductal dilatation. conniventes (arrowheads). In addition, a homoge- Differential considerations for duodenal ulcers neously enhancing exophytic mass arising from the un- cinate process and head of the pancreas is seen during include acid exposure, acid-producing tumors the arterial phase (arrow). (the Zollinger–Ellison syndrome), or . In addition, the differential consider- ations for solid tumors of the pancreas should consists of grades I through V, with grade V in- always include pancreatic , me- dicating the metaplasia seen in Barrett’s esopha- tastases (most commonly from renal-cell carci- gus); excessive fluid (1600 ml) in the gastric body; noma or melanoma, and occasionally from ovar- a partially obstructing duodenal ulcer (30 mm in ian cancer), and neuroendocrine tumors. Classic

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duodenal-biopsy specimen did not show the vil- intestinal peptide–producing tumor (VIPoma), lous atrophy that is the signature pathological and gastrinoma. The absence of flushing makes feature of celiac disease.7 His clinical picture is carcinoid tumor less likely. VIPoma is classically most notable for chronic watery stools. associated with profound hypokalemia and hypo- chlorhydria, which were not present.10 Chronic watery diarrhea Gastrinoma warrants serious consideration. On Measurement of the stool for electrolyte levels is the patient’s second upper endoscopy, the finding informative in this case, as is calculation of the of a large duodenal ulcer with a crater, as well (the difference between stool as multiple smaller ulcers, raises concern for osmolality, in milliosmoles per kilogram of wa- gastric-acid hypersecretion. This patient had a ter, and twice the sum of the stool sodium and negative test for H. pylori antibody and did not use potassium levels, in millimoles per liter). A stool nonsteroidal antiinflammatory drugs, ruling out osmotic gap8 of less than 50 strongly suggests a the two most common causes of peptic ulcer dis- secretory diarrhea, and an osmotic gap of more ease.11 Ulcers developed despite his regular use than 125 suggests osmotic diarrhea; this patient’s of a proton-pump inhibitor, which is an unusual calculated stool osmotic gap was in the low- finding that deserves further investigation. intermediate range at 70, with a high level of so- Gastrinoma, a rare tumor of the pancreas and dium in the stool, suggesting that a secretory pro- duodenum, causes ectopic hypersecretion of gas- cess is more likely than osmotic diarrhea. trin and results in the hypersecretion of gastric The differential diagnosis of secretory diar- acid, leading to severe peptic ulcer disease; this rhea includes infections, structural diseases, en- complex of findings is known as the Zollinger– docrinopathy, and peptide-secreting tumors. An Ellison syndrome12 and is often accompanied by infectious cause of secretory diarrhea has been esophageal reflux disease and diarrhea. I am satisfactorily ruled out. Structural bowel disease, particularly mindful that on this patient’s first including intestinal and pancreatic tumors and upper endoscopy (2 years before admission), men- inflammatory bowel disease, should be evaluated tion was made of a prominent gastric fold, an with CT of the abdomen, small-bowel enteros- unusual finding. In one series, a prominent gas- copy, and colonoscopy. tric fold was found in more than 90% of patients This patient was appropriately evaluated for with the Zollinger–Ellison syndrome.13 The fac- the most common endocrinologic causes of diar- tors that contribute to gastrinoma-associated di- rhea, including diabetes mellitus, hyperthyroid- arrhea are a high volume of ; inacti- ism, and adrenal insufficiency. Systemic masto- vation of pancreatic digestive enzymes by gastric cytosis could be a unifying diagnosis for peptic acid, causing ; and inhibition of sodi- ulcer disease and diarrhea; however, the absence um and water reabsorption by the small intestine, of a history of urticaria and the absence of find- causing a secretory diarrhea.10 ings of mast-cell infiltration on examination of Gastrinoma is slightly more common in men the previous esophageal-biopsy specimens make than in women, and the age at onset is generally this diagnosis unlikely.9 between 41 and 53 years of age.10 On average, A rare, but important, class of chronic secretory the diagnosis is made 5 years after the onset of diarrheal illnesses is caused by peptide-secreting symptoms.13 This patient was 51 years of age at tumors. Because these tumors are uncommon, a the onset of his symptoms, which is typical. critical approach to the patient’s history and Twenty to 25% of patients with gastrinoma have other clinical features is essential before labora- the multiple endocrine neoplasia type 1 (MEN-1) tory testing for these peptides is undertaken. The syndrome. Almost all patients with MEN-1 have screening panels for these tumors are far more primary hyperparathyroidism.13,14 I would review likely to produce false positive than true positive this patient’s history for any previous episodes results.4 of kidney stones and for a family history of en- docrine tumors. Since this patient’s calcium Peptide-Secreting Tumors levels remained normal, even when he was in a The major peptide-secreting tumors to be consid- volume-depleted state, it is unlikely that he had ered in this patient are carcinoid tumor, vasoactive hyperparathyroidism.

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Testing for gastrinoma starts with measure- CLINICAL DIAGNOSIS ment of a fasting serum level. The gastrin level is elevated in virtually all patients with the of the pancreas. Zollinger–Ellison syndrome; therefore, a normal level essentially rules out this condition. How- DR. LEIGH H. SIMMONS’s DIAGNOSIS ever, our measurements could be confounded by the patient’s recent use of proton-pump inhibitors, Sporadic (non–multiple endocrine neoplasia type 1) which can raise the fasting gastrin levels mark- Zollinger–Ellison syndrome (gastrinoma). edly.15 This patient’s gastric-outlet obstruction could also raise gastrin levels, as could peptic ulcer PATHOLOGICAL DISCUSSION disease itself. In this circumstance, it would be helpful to either stop the proton-pump inhibitors Dr. Lawrence R. Zukerberg: We received a specimen for a week before measuring gastrin (which could from the surgical resection of the pancreatic mass. present a therapeutic challenge because of the The specimen consisted of a segment of distal severe peptic ulcer disease) or perform a provoca- stomach, 6.5 cm in length, attached to a segment tive test involving the intravenous injection of of duodenum, 25 cm in length, surrounding the and the subsequent measurement of the head of the pancreas, which contained a mass gastrin level. I would first perform a fasting gas- that measured 6.2 cm in diameter. An ulcer (2 cm trin test, and if it is elevated, I would perform a in diameter) without heaped-up edges was pres- secretin stimulation test. A gastrin level that in- ent in the proximal duodenum (Fig. 2A). The creases by more than 120 pg per milliliter in re- pancreatic mass was circumscribed and was com- sponse to secretin is diagnostic of a gastrinoma.16 posed of firm, white tissue and darker, more hem- Furthermore, on review of this patient’s im- orrhagic tissue adjacent to the normal-appearing aging studies, we learn that there was concern yellow-tan pancreas (Fig. 2B). Microscopically, about a pancreatic mass. Such a finding, in com- nests of tumor cells were separated by fibrous bination with the patient’s clinical presentation, tissue. The tumor cells were relatively uniform makes gastrinoma the most likely explanation for and round, with pink cytoplasm and central round the illness. In addition to measurement of a fast- nuclei with the fine “salt and pepper” chromatin ing serum gastrin level, I suspect that a biopsy that is characteristic of neuroendocrine cells of the pancreatic mass was also performed. (Fig. 2C). Immunohistochemical staining of the Dr. Eric S. Rosenberg (Pathology): May we have tumor cells was positive for gastrin (Fig. 2D). the medical students’ diagnosis? The World Health Organization distinguishes Harvard Medical School Student: Our top consid- among three grades of neuroendocrine tumors. erations were a neuroendocrine tumor, infectious Grades 1 and 2 consist of well-differentiated tu- diarrhea, or an autoimmune gastrointestinal dis- mors, and grade 3 consists of poorly differentiated ease such as inflammatory bowel disease or ce- tumors, including small-cell . Grade 1 liac disease. Given the patient’s history of chron- and grade 2 are separated by mitoses and the ic secretory diarrhea, multiple peptic ulcers, and proliferation index, assessed with Ki67 immu- Barrett’s esophagus, we favor gastrinoma as the nostaining. Other predictive factors include the most likely diagnosis. stage and size and whether invasion is perineu- Dr. Rosenberg: Dr. Forrester, what was your ral or vascular. The tumor in this case had fewer clinical impression when you saw this patient? than two mitoses per 10 high-power fields, had Dr. Forrester: We initially focused on infection a Ki67 index of less than 3%, and expressed the and inflammatory bowel disease as possible neuroendocrine markers chromogranin and syn- causes of his syndrome. We were also intrigued aptophysin, as well as gastrin. Thus, the tumor by the association of the diarrhea with air travel is classified as a well-differentiated pancreatic and wondered whether changes in atmospheric neuroendocrine neoplasm (gastrinoma), grade 1. pressure had a role in unmasking his symptoms. Lymphatic invasion was present, the margins were However, we were most concerned about the negative, and 4 out of 31 lymph nodes were pancreatic mass and thought a neuroendocrine positive. On the basis of size and the involvement tumor was likely. of peripancreatic tissue, as well as the number of

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A B

C D

Figure 2. Pancreatic Mass. A specimen obtained from surgical resection of the pancreatic mass shows an ulcer, 2 cm in diameter and without heaped-up edges, in the proximal duodenum (Panel A). There is a circumscribed, dark-red-and-white mass adjacent to lobulated yellow-tan pancreas (Panel B). Microscopical examination of a section of the pancreatic mass shows nests of neuroendocrine-appearing cells with round nuclei and fine chromatin (Panel C, hematoxylin and eosin), and immunohistochemical staining of some of the tumor cells is positive for gastrin (Panel D).

positive lymph nodes, the stage was determined cases of a close or positive surgical margin, but to be pT3N1Mx. there is a paucity of data to support such therapy. Serum gastrin levels measured at the time of Our standard approach is to offer radiotherapy in surgery were markedly elevated, at 1329 pg per combination with to serve as a ra- milliliter (reference range, <100). After surgery, diation sensitizer. In this patient, we were unable the gastrin levels have remained normal. There- to initiate adjuvant therapy for about 3 months fore, the final diagnosis in this case is the because a fluid collection developed that required Zollinger–Ellison syndrome, caused by pancre- percutaneous drainage. Postoperative imaging atic gastrin-secreting neuroendocrine neoplasm revealed a residual paraaortic lymph node. In pa- (gastrinoma). tients with adenocarcinoma of the pancreas, re- moval of lymph nodes away from the primary FOLLOW-UP tumor is unlikely to have a meaningful effect on the clinical outcome. However, in patients with Dr. Lawrence S. Blaszkowsky (Hematology–Oncolo- pancreatic neuroendocrine tumors, we generally gy): I was asked to see the patient to assess the attempt to remove all disease because of the need for adjuvant therapy because of a posterior more favorable biologic features of the disease. (retroperitoneal) margin of less than 1 mm. In this patient, a residual focus of gastrin secre- There is no established role for adjuvant therapy tion might have influenced the morbidity and in this disease. We consider adjuvant therapy in quality of life. The surgeon believed that removal

764 n engl j med 368;8 nejm.org february 21, 2013 The New England Journal of Medicine Downloaded from nejm.org by NASER DARIANI on September 24, 2013. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. case records of the massachusetts general hospital of this lymph node would be technically chal- than 50%. Recurrence is possible, but neuroen- lenging and favored proceeding with chemora- docrine tumors tend to be relatively indolent as diation as planned. compared with adenocarcinoma. Agents such as Approximately 3 weeks after the completion of sunitinib and everolimus may be options for this chemoradiation, the patient presented to another patient if the disease recurs. hospital with severe abdominal pain, and imag- ing studies suggested a perforated viscus. He was ANATOMICAL DIAGNOSIS transferred to this hospital, and the surgeon re- paired the ulcer and removed the residual lymph Gastrinoma. node that had been seen on postoperative imag- This case was presented as part of the Medicine Case Confer- ing. Twenty months after chemoradiation, the ence series. We thank Dr. Nesli Basgoz for review of the case patient is doing well. The gastrin level is normal, history. and he has no evidence of recurrent disease. Dr. Simmons reports receiving consulting fees from New England Research Institute; and Dr. Zukerberg, receiving con- Dr. Nancy Lee Harris (Pathology): What is this sulting fees from Immunogen and providing expert testimony patient’s long-term prognosis, given the positive for law firms and insurance groups on cases related to leukemia, lymph nodes and a large tumor? lymphoma, and gastrointestinal . No other potential con- flict of interest relevant to this article was reported. Dr. Blaszkowsky: The estimated 5-year survival Disclosure forms provided by the authors are available with rate among patients with regional disease is more the full text of this article at NEJM.org.

References

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