Case 8-2004 — A 28-Year-Old Man with Abdominal Pain, Fever, and a Mass in the Region of the Pancreas
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《新英格兰医药杂志》
Presentation of Case
A 28-year-old man was admitted to the hospital because of abdominal pain and fever.
The patient had been well until 10 days earlier, when mild epigastric pain developed. Two days before admission, the abdominal pain, which was now localized in the right upper and right lower quadrants, became constant and severe, and nausea developed, without vomiting. He passed a stool on the day of admission and had chills without frank rigors. The patient had no history of abdominal surgery, diarrhea, hematochezia, melena, or contact with ill persons. He smoked cigarettes but did not drink alcohol. He was a native of a small city in Morocco and had immigrated to the United States 13 months before admission.
The temperature was 38.3°C, the pulse 89 beats per minute, and the respiratory rate 18 breaths per minute. The blood pressure was 110/65 mm Hg.
On physical examination, the patient did not appear to be in severe pain, and there was no jaundice. The lungs and heart sounds were normal. The abdomen was flat, and bowel sounds were present. There was tenderness in the right upper and right lower quadrants, with guarding and rebound tenderness. No mass or hernia was detected. The arms and legs were well perfused. No abnormalities were found on rectal examination, and a stool specimen was negative for occult blood.
The urine was positive (+) for ketones; the sediment contained up to 2 red cells, 3 to 5 white cells, and a few bacteria per high-power field. The total protein level was 8.1 g per deciliter (albumin, 3.9 g per deciliter; globulin, 4.2 g per deciliter). The levels of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, electrolytes, aspartate aminotransferase, alanine aminotransferase, amylase, lipase, alkaline phosphatase, and gastrin were normal. Other laboratory values are shown in Table 1. A serologic test for Helicobacter pylori was positive.
Table 1. Hematologic Laboratory Data on Admission.
Radiographs of the abdomen obtained both while the patient was supine and while he was upright showed air-filled loops of small bowel, without dilatation or air–fluid levels. No free intraperitoneal air was visible. No abnormal calcifications were identified, and the bones were unremarkable. Abdominal and pelvic computed tomographic (CT) studies, performed after the oral and intravenous administration of contrast material, revealed a heterogeneously enhancing, multicystic structure, 4.2 by 2.9 cm, cephalad to the pancreatic head. A cystic mass, 1.5 cm in diameter, was contiguous with the head and neck of the pancreas. The remainder of the pancreas was unremarkable. The liver, spleen, gallbladder, adrenal glands, kidneys, distal small bowel, colon, urinary bladder, and imaged bones were unremarkable, and no retroperitoneal lymphadenopathy was evident.
Oral intake was stopped. The patient was given fluid and electrolytes as well as ranitidine, metronidazole, ampicillin, minidose heparin, and morphine, which was administered by a patient-controlled analgesia device. On the second hospital day, the temperature was 39.2°C. On esophagogastroduodenoscopic examination with endoscopic ultrasonography, the esophagus, stomach, and duodenum appeared normal. The pancreatic head contained parenchymal abnormalities that consisted of hyperechoic strands, hypoechoic foci, and lobules. An irregular, hypoechoic, heterogeneous, lobular mass with both solid and cystic components, 4.0 by 2.9 cm, lay adjacent to the neck of the pancreas; its origin was obscure, and its outer margins were poorly defined. Examination of a specimen obtained by fine-needle aspiration disclosed no malignant tumor cells. There was abundant acute inflammation, with focal areas of chronic inflammation and reactive ductal epithelium — findings suggestive of an abscess.
The maximal temperature on the third hospital day was 38.6°C, and on the fourth hospital day it was 38.3°C. Another abdominal and pelvic CT study, performed according to a special protocol to delineate the pancreas and peripancreatic area more clearly, again showed a complex, multicystic mass, approximately 3.2 by 5.1 cm, that was contiguous with the pancreatic head (Figure 1). The splenic, superior mesenteric, and portal veins and the celiac and superior mesenteric arteries were patent and not encased. By the sixth hospital day, the temperature had fallen to 37.6°C, and no analgesia was required.
Figure 1. Consecutive Images from a CT Study of the Abdomen and Pelvis, Performed According to a Special Protocol for the Evaluation of the Pancreas.
Panel A shows multiple small, cystic nodules in the periportal area (arrow). Panel B, which shows an area slightly caudal to that in Panel A, depicts the contiguity of the nodules (arrowhead) to the pancreas (arrow).
A diagnostic procedure was performed.
Differential Diagnosis
Dr. William R. Brugge: May we review the radiographs?
Dr. Peter R. Mueller: A specialized CT study was performed with images taken at various times during the administration of the bolus of contrast material. Imaging during different phases of opacification allows the best view of the pancreas, the peripancreatic tissues, and their relationship to the surrounding vasculature. We used very thin (1.2 mm) imaging slices to allow reconstruction in a three-dimensional plane and to allow detailed analysis of the relevant anatomical features. The scan (Figure 1) revealed multiple cystic nodules of various sizes in the region of the porta hepatis. In the region of the head and neck of the pancreas, these small cystic nodules are contiguous with but separate from the pancreas. The portal vein and superior mesenteric artery are patent and unremarkable. The tail of the pancreas is normal. The pancreatic and bile ducts are not dilated. No lymphadenopathy was seen, and no other specific abnormalities in other organs were detected. There was a small amount of ascites in the pelvis.
Dr. Brenna C. Bounds (Gastroenterology): The endoscopic ultrasonographic study revealed a heterogeneous, mixed lesion with both solid and cystic components; it appeared to be adjacent to the pancreas but not to involve the pancreas directly. Fine-needle aspiration of the lesion was performed.
Dr. Brugge: This previously healthy young man from Morocco began to have symptoms 10 days before admission. His chief problem was abdominal pain, which became severe and localized to the right upper quadrant two days before admission. This information suggests a relatively acute illness, as opposed to a chronic, progressive illness such as chronic pancreatitis. The chills and a low-grade fever suggest the presence of an infectious or a highly malignant process, such as lymphoma. The absence of jaundice is helpful, since it is evidence that the patient's illness is not caused by a bile-duct stone. Moreover, acute biliary obstruction as a result of a bile-duct stone would be unusual in a young man. A patient with acute cholecystitis could present with a 10-day history of increasing abdominal pain without evidence of biliary obstruction; a patient with a liver abscess could present with subacute right upper quadrant abdominal pain and a low-grade fever. With these possibilities in mind, we can obtain additional information from the physical examination.
There was tenderness to the point of guarding and rebound tenderness in the right upper quadrant. These findings are highly suggestive of acute cholecystitis or a liver abscess. However, there was no evidence of a Murphy sign (i.e., a pause in the normal respiratory motion during inspiration and compression of the right upper quadrant). The liver did not appear to be enlarged, and there was no elevation of the right hemidiaphragm. The absence of blood in the stool argues against an active inflammatory or peptic process in the duodenum. Since there is no mention of spider angiomata, palmar erythema, or splenomegaly, chronic liver disease also seems to be an unlikely diagnosis.
The results of initial laboratory tests included a normal hematocrit but an increased white-cell count. The amylase and lipase levels were normal. The results of liver-function tests were also normal. These findings are important because they essentially rule out the possibility of acute pancreatitis, cholangitis, or a liver abscess. The normal results of the liver-function tests also make the possibility of severe acute cholecystitis very unlikely. Finally, a serologic test for H. pylori was positive, which may indicate the presence of an active infection or a previous exposure.
I shall turn to the information provided by the radiographic studies. The abdominal films show that there were no pancreatic, splenic, or liver parenchymal calcifications and no small-bowel obstruction. The CT scan obtained on the first day showed a large, complex, partially cystic mass involving the neck of the pancreas and the porta hepatis. The lesion appeared to be adjacent to the pancreas. There was no evidence of biliary obstruction, and the bile duct and gallbladder appeared to be intact and free of stones or infection. The liver was normal, and there was no evidence of cirrhosis, ascites, or an abscess. The cystic lesions were somewhat enhanced after the intravenous administration of contrast material.
Cystic Lesions of the Pancreas
Many cystic lesions of the pancreas might explain these findings. The most common cystic lesion of the pancreas is a rapid collection of fluid, which usually develops in association with acute pancreatitis.1 Acute peripancreatic fluid collections are usually well-demarcated areas adjacent to the pancreas and are composed of inflammatory debris and fluid derived from the pancreas.2 Since these fluid collections are not vascular, there is little enhancement after the administration of contrast material during CT scanning.3 In the case under discussion, the finding of a completely normal pancreas on CT scanning is further evidence that the cystic lesion in question does not represent a complication of acute pancreatitis.
Two cystic lesions of the pancreas — serous cystadenoma and islet-cell tumor of the pancreas — are enhanced after the administration of contrast material. Serous cystadenomas are most commonly microcystic, with a honeycombed appearance.4 They are benign and rarely cause symptoms. The increased vascularity of these lesions recognized on CT scanning is a result of a lush capillary network running along the walls of the cysts.5 Recently, it has been noted that nearly one third of serous cystadenomas are macrocystic and mimic mucinous cystic lesions. Only about 20 percent have the central stellate calcifications that are diagnostic of serous cystadenomas. I think that the CT appearance of the cystic lesion in the current case and the patient's clinical features on presentation make a serous cystadenoma very unlikely.
Islet-cell tumors of the pancreas may occasionally take the form of a complex cystic mass. They are very vascular and have an arterially enhancing feature that is obvious during CT scanning.6 When the tumors are cystic, rim enhancement may be visible on CT scans. The lesions may be quite heterogeneous, because of spontaneous bleeding and necrosis within the tumor. Most of them are nonfunctioning.7 However, islet-cell tumors are most commonly located in the tail of the pancreas, and they are usually solid. It would be very unusual for a patient with a cystic islet-cell tumor to present with right upper quadrant pain and rebound tenderness.
A rare cystic tumor of the pancreas is the solid cystic pseudopapillary tumor.8 This lesion appears to be a variant of a neuroendocrine tumor and usually occurs in young women.9 Many of these tumors have progesterone receptors. Although they may be very large, these tumors rarely cause symptoms. Most are not vascular and are not enhanced after the injection of contrast material.10 For these reasons, I am eliminating a solid cystic pseudopapillary tumor of the pancreas from the differential diagnosis in this case.
The last cystic lesion to be considered is a mucinous lesion, such as a mucinous cystadenoma or an intraductal papillary mucinous tumor. Mucinous cystadenomas arise from mucinous epithelium within the pancreatic parenchyma but are often associated with ovarian-type stroma adjacent to the cystic lesion.11 These lesions are commonly found in young women and rarely in young men. Furthermore, they are not classically enhanced on CT scanning.5 A malignant mucinous cystic neoplasm could have many of the features seen on this patient's CT scan.12 However, it would be unusual for a young man to present with this type of malignant lesion and with subacute abdominal pain. A pancreatic lymphoma is another possibility, since such a lesion might enhance on CT scanning and could cause severe abdominal pain and fever, but lymphomas are typically solid lesions.13
The clinicians caring for this patient chose to treat him initially with ranitidine, metronidazole, ampicillin, minidose heparin, and morphine, which was given by means of a patient-controlled analgesia device. They must have been concerned that his pain arose from a complication of H. pylori infection. The use of morphine indicates the severity of the abdominal pain and suggests the presence of an active, acute process from an infection or a rapidly expanding malignant tumor. The decision was made to obtain tissue from the lesion by fine-needle aspiration during endoscopic ultrasonography. This was a wise choice, since obtaining a biopsy specimen of the lesion during CT scanning would probably have been difficult.14
The ultrasonographic examination revealed a large, complex, heterogeneous lesion adjacent to the pancreas. The parenchyma in the head of the pancreas was abnormal, with an appearance suggestive of early chronic pancreatitis. The complex, cystic lesion was poorly defined and was not a discrete lesion within the pancreas. Instead, it appeared to be located in the peripancreatic area and extended superiorly to the porta hepatis. These findings are consistent with the possible presence of a malignant lesion, such as a lymphoma or a mucinous cystadenocarcinoma, or an inflammatory process, such as a peripancreatic fluid collection. A primary infection of the pancreas, such as cytomegalovirus pancreatitis, a bacterially infected peripancreatic fluid collection, or a granulomatous process arising from tuberculosis or infection with atypical mycobacteria, is also possible.
Infectious Processes
Bacterial, Fungal, or Viral Infection
The next clues come from the cytologic features of the aspiration specimen. The finding of acute inflammatory cells in the aspirate strongly suggests that the process is not a malignant one. The absence of intranuclear inclusions in the epithelial cells is evidence against a viral cause. Another possibility is primary bacterial or fungal infection of the pancreas. Primary fungal infections of the pancreas are rare and are usually associated with acute pancreatitis and necrosis. Candida albicans is the most common causative organism and would have been seen in the aspirate. Furthermore, it would be very unusual for a young, otherwise healthy man to have a primary candidal infection of the pancreas.15 Such an infection could be a possibility if the patient were positive for the human immunodeficiency virus (HIV). However, we know nothing about his risk factors for HIV infection, and we do not have results of HIV testing.
A repeated CT scan was performed with the use of thin slices, with attention to the pancreas. Again, a complex cystic lesion was identified in or adjacent to the pancreas. There was no evidence of vascular invasion, suggesting that this process was nonneoplastic in nature.
Mycobacterial Infection
The last type of infection we should consider is a primary mycobacterial infection of the pancreas or adjacent lymphoid tissue.16 This rare infection usually starts in the peripancreatic lymph nodes and initially spares the pancreas.17 Lesions resulting from mycobacterial infection of the pancreas are often complex and cystic, and they mimic cystic neoplasms of the pancreas.18,19 Their cystic nature and the finding of rim enhancement on CT studies probably reflect the presence of central necrosis within the infected lymph nodes.20 The absence of inflammatory changes in the mesentery and jejunum and the absence of enlargement of the liver and spleen point to infection with Mycobacterium tuberculosis rather than M. avium complex.21 Mycobacterial infection of the pancreas causes fever, pain, and abdominal tenderness.
If left untreated, mycobacterial infection of the pancreas is highly lethal, but it is responsive to antimycobacterial agents. Most cases are not diagnosed preoperatively, since special staining of biopsy specimens is necessary and since cultures of the aspirate require prolonged incubation.22 Fine-needle aspiration has been used to diagnose the presence of acid-fast bacilli in lesions of the pancreas, but only with the use of mycobacterial stains.23 Findings on examination of fine-needle aspiration samples are diagnostic in only 30 to 40 percent of cases.
In Morocco, tuberculosis is a widespread public health problem, with an annual incidence of more than 100 infections per 100,000 people.24 When immigrants from a country where the risk is high settle in developed countries, they may be responsible for outbreaks of infection. In the Netherlands, it was estimated that 17 percent of the cases of tuberculosis could be traced to infected immigrants, and among these immigrants Morocco was the second most common country of origin.24
The diagnostic procedure in this patient could have been Ziehl–Neelsen staining of the material obtained by fine-needle aspiration, which would have disclosed the presence of mycobacteria. If these stains did not reveal acid-fast bacilli, a laparotomy would have been necessary to obtain diagnostic tissue.
Dr. Nancy Lee Harris (Pathology): I would like to invite the medical students to discuss the differential diagnosis.
Adam Cohen (Harvard Medical School student): The differential diagnosis of cystic pancreatic masses includes pseudocysts, cystadenomas, and cystic malignant tumors. In a previously healthy young man with fever and spreading of the mass beyond the pancreas, we believe that none of these lesions is likely. The radiologic findings are more consistent with a mass of lymph-node origin that is adjacent to, but does not actually involve, the pancreas. The differential diagnosis of cystic lymphadenopathy includes infectious diseases, sarcoidosis, lymphoma, and rare disorders such as Whipple's disease. Given the acute onset and the inflammatory changes found on examination of the fine-needle aspiration specimen, we believe that an infectious cause is likely. Since tuberculosis is endemic in Morocco, the most likely diagnosis is abdominal abscess from M. tuberculosis infection. The diagnostic procedure could be acid-fast staining of the fine-needle aspirate for mycobacteria; it also could be subtotal pancreatectomy, removal of the abscess, and acid-fast staining of the surgical specimen.
Clinical Diagnosis
Pancreatic mass, cystic neoplasm, or abscess.
Dr. William R. Brugge's Diagnosis
Mycobacterium tuberculosis infection of the peripancreatic lymph nodes.
Pathological Discussion
Dr. Joseph Misdraji: The specimen obtained by fine-needle aspiration showed signs of acute and chronic inflammation, consistent with the presence of an abscess. Neither histiocytic multinucleated giant cells nor granulomas were seen. An acid-fast stain was not performed on that specimen because it lacked a granulomatous component, and it was not sent for microbiologic culture.
Dr. Steven Abbate performed a laparotomy. A cavitated lesion beneath the liver was unroofed as the edge of the liver was lifted, and portions of it were sent for Gram's staining and culture. The intraoperative Gram's stain was negative. Further inspection disclosed a mass, 3 cm in diameter, adherent to the superior aspect of the pancreas at the level of the neck (Figure 2). A distal pancreatectomy was performed to excise the mass. An enlarged celiac lymph node was also removed.
Figure 2. Photograph of the Gross Specimen Obtained during Distal Pancreatectomy.
The mass, 3 cm in diameter, had been located at the level of the pancreatic neck. The cut surface is mottled white, tan, and brown and contains cystic areas lined by tan, granular, necrotic-appearing tissue.
The cut surface of the mass was mottled white, tan, and brown and contained several necrotic, cystic areas. On histologic examination, the mass was found to consist of matted lymph nodes with numerous granulomas, many of which contained central caseous necrosis (Figure 3). Areas of extensive necrosis surrounded by palisading histiocytes were also present. The inflammatory process extended a short distance into the pancreas. Despite multiple attempts, we were unable to identify organisms on acid-fast stains or silver stains. A diagnosis of necrotizing granulomatous lymphadenitis involving the peripancreatic and celiac lymph nodes was made. The celiac lymph node also contained necrotizing granulomas. Subsequently, cultures yielded M. tuberculosis complex. Therefore, the final pathological diagnosis was tuberculous lymphadenitis involving the peripancreatic lymph nodes, with associated chronic pancreatitis.
Figure 3. Photomicrographs of the Specimen Obtained during Distal Pancreatectomy (Hematoxylin and Eosin).
Microscopical examination shows that the mass consists of matted lymph nodes with granulomatous lymphadenitis (Panel A, x100); in areas (right), the granulomas coalesce. Many of the granulomas contain amorphous, eosinophilic, granular debris, indicating caseation necrosis (Panel B, x200). Panel C (x200) shows the edge of a large necrotic zone (top right) that is lined by palisading histiocytes. Panel D (x100) shows that the inflammatory process extends from the peripancreatic lymph nodes (right) into the pancreas (left) and is characterized by inflammation, fibrosis, and acinar atrophy. A residual islet of Langerhans is present (top left).
Some of the reported cases of pancreatic tuberculosis may actually represent cases of tuberculosis in the peripancreatic lymph nodes, as in this case. Tuberculosis can affect the pancreas either by contiguous spread from the peripancreatic lymph nodes or by hematogenous spread.25 Patients with pancreatic tuberculosis most often present with a pancreatic mass mimicking a carcinoma,25 although they may also present with acute pancreatitis, a chronic pancreatic abscess, obstructive jaundice, or gastrointestinal bleeding.26,27,28,29,30
Pancreatic tuberculosis is rare, even in countries where tuberculosis is endemic. Most often, it occurs in the setting of miliary tuberculosis. In two large studies, the incidence of pancreatic tuberculosis in patients with miliary tuberculosis was 2.1 percent and 4.7 percent.31,32 Pancreatic tuberculosis without involvement of other sites is exceptionally rare; fewer than 30 cases have been reported.
The rarity of pancreatic tuberculosis may be due to the fact that the pancreas appears to be somewhat resistant to M. tuberculosis infection. Intrapancreatic injections of M. tuberculosis cause pancreatic lesions only when large inocula are used. Several investigators have shown that pancreatic extracts and purified lipases and DNAses have antimycobacterial properties.33
Dr. Harris: Dr. Kotton, you saw the patient after the operation. Will you tell us about his treatment and subsequent course?
Dr. Camille N. Kotton (Infectious Disease): When my colleagues and I saw the patient, he had recovered from the operation and had been discharged, but he later returned to the hospital because of persistent low-grade fevers. Because of the pathologic findings of granulomas, we were very concerned about tuberculosis, although the culture results were still pending. Additional serologic tests for antibodies to HIV types 1 and 2, brucella, schistosoma, and echinococcus were all negative. Ruling out these infections was helpful, given the rarity of tuberculosis of the pancreas. We believed this patient probably had tuberculosis, and we initiated a four-drug regimen. Once his cultures grew M. tuberculosis and the isolate was found to be pan-sensitive, we reduced the four-drug regimen to a two-drug regimen. He was treated with that regimen for six months and tolerated it well.
Dr. Harris: Is the disease in this case a manifestation of primary gastrointestinal tuberculosis, a primary infection of lymph nodes surrounding the gut, or reactivation of old disease with hematogenous spread to the upper abdominal lymph nodes?
Dr. Kotton: I would assume that it is a reactivation of tuberculosis acquired while the patient was living in Morocco. On further questioning, he told us his brother had had active tuberculosis at some point during his childhood. It is not known why his disease reactivated at this time.
Anatomical Diagnosis
Tuberculous lymphadenitis involving the peripancreatic lymph nodes.
Addendum
One year after completing antituberculosis therapy, the patient was in good health, and no further lesions were seen on repeated abdominal CT scanning.
Source Information
From the Gastroenterology Unit, Department of Medicine (W.R.B.), and the Departments of Radiology (P.R.M.) and Pathology (J.M.), Massachusetts General Hospital; and the Departments of Medicine (W.R.B.), Radiology (P.R.M.), and Pathology (J.M.), Harvard Medical School.
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A 28-year-old man was admitted to the hospital because of abdominal pain and fever.
The patient had been well until 10 days earlier, when mild epigastric pain developed. Two days before admission, the abdominal pain, which was now localized in the right upper and right lower quadrants, became constant and severe, and nausea developed, without vomiting. He passed a stool on the day of admission and had chills without frank rigors. The patient had no history of abdominal surgery, diarrhea, hematochezia, melena, or contact with ill persons. He smoked cigarettes but did not drink alcohol. He was a native of a small city in Morocco and had immigrated to the United States 13 months before admission.
The temperature was 38.3°C, the pulse 89 beats per minute, and the respiratory rate 18 breaths per minute. The blood pressure was 110/65 mm Hg.
On physical examination, the patient did not appear to be in severe pain, and there was no jaundice. The lungs and heart sounds were normal. The abdomen was flat, and bowel sounds were present. There was tenderness in the right upper and right lower quadrants, with guarding and rebound tenderness. No mass or hernia was detected. The arms and legs were well perfused. No abnormalities were found on rectal examination, and a stool specimen was negative for occult blood.
The urine was positive (+) for ketones; the sediment contained up to 2 red cells, 3 to 5 white cells, and a few bacteria per high-power field. The total protein level was 8.1 g per deciliter (albumin, 3.9 g per deciliter; globulin, 4.2 g per deciliter). The levels of urea nitrogen, creatinine, glucose, conjugated and total bilirubin, electrolytes, aspartate aminotransferase, alanine aminotransferase, amylase, lipase, alkaline phosphatase, and gastrin were normal. Other laboratory values are shown in Table 1. A serologic test for Helicobacter pylori was positive.
Table 1. Hematologic Laboratory Data on Admission.
Radiographs of the abdomen obtained both while the patient was supine and while he was upright showed air-filled loops of small bowel, without dilatation or air–fluid levels. No free intraperitoneal air was visible. No abnormal calcifications were identified, and the bones were unremarkable. Abdominal and pelvic computed tomographic (CT) studies, performed after the oral and intravenous administration of contrast material, revealed a heterogeneously enhancing, multicystic structure, 4.2 by 2.9 cm, cephalad to the pancreatic head. A cystic mass, 1.5 cm in diameter, was contiguous with the head and neck of the pancreas. The remainder of the pancreas was unremarkable. The liver, spleen, gallbladder, adrenal glands, kidneys, distal small bowel, colon, urinary bladder, and imaged bones were unremarkable, and no retroperitoneal lymphadenopathy was evident.
Oral intake was stopped. The patient was given fluid and electrolytes as well as ranitidine, metronidazole, ampicillin, minidose heparin, and morphine, which was administered by a patient-controlled analgesia device. On the second hospital day, the temperature was 39.2°C. On esophagogastroduodenoscopic examination with endoscopic ultrasonography, the esophagus, stomach, and duodenum appeared normal. The pancreatic head contained parenchymal abnormalities that consisted of hyperechoic strands, hypoechoic foci, and lobules. An irregular, hypoechoic, heterogeneous, lobular mass with both solid and cystic components, 4.0 by 2.9 cm, lay adjacent to the neck of the pancreas; its origin was obscure, and its outer margins were poorly defined. Examination of a specimen obtained by fine-needle aspiration disclosed no malignant tumor cells. There was abundant acute inflammation, with focal areas of chronic inflammation and reactive ductal epithelium — findings suggestive of an abscess.
The maximal temperature on the third hospital day was 38.6°C, and on the fourth hospital day it was 38.3°C. Another abdominal and pelvic CT study, performed according to a special protocol to delineate the pancreas and peripancreatic area more clearly, again showed a complex, multicystic mass, approximately 3.2 by 5.1 cm, that was contiguous with the pancreatic head (Figure 1). The splenic, superior mesenteric, and portal veins and the celiac and superior mesenteric arteries were patent and not encased. By the sixth hospital day, the temperature had fallen to 37.6°C, and no analgesia was required.
Figure 1. Consecutive Images from a CT Study of the Abdomen and Pelvis, Performed According to a Special Protocol for the Evaluation of the Pancreas.
Panel A shows multiple small, cystic nodules in the periportal area (arrow). Panel B, which shows an area slightly caudal to that in Panel A, depicts the contiguity of the nodules (arrowhead) to the pancreas (arrow).
A diagnostic procedure was performed.
Differential Diagnosis
Dr. William R. Brugge: May we review the radiographs?
Dr. Peter R. Mueller: A specialized CT study was performed with images taken at various times during the administration of the bolus of contrast material. Imaging during different phases of opacification allows the best view of the pancreas, the peripancreatic tissues, and their relationship to the surrounding vasculature. We used very thin (1.2 mm) imaging slices to allow reconstruction in a three-dimensional plane and to allow detailed analysis of the relevant anatomical features. The scan (Figure 1) revealed multiple cystic nodules of various sizes in the region of the porta hepatis. In the region of the head and neck of the pancreas, these small cystic nodules are contiguous with but separate from the pancreas. The portal vein and superior mesenteric artery are patent and unremarkable. The tail of the pancreas is normal. The pancreatic and bile ducts are not dilated. No lymphadenopathy was seen, and no other specific abnormalities in other organs were detected. There was a small amount of ascites in the pelvis.
Dr. Brenna C. Bounds (Gastroenterology): The endoscopic ultrasonographic study revealed a heterogeneous, mixed lesion with both solid and cystic components; it appeared to be adjacent to the pancreas but not to involve the pancreas directly. Fine-needle aspiration of the lesion was performed.
Dr. Brugge: This previously healthy young man from Morocco began to have symptoms 10 days before admission. His chief problem was abdominal pain, which became severe and localized to the right upper quadrant two days before admission. This information suggests a relatively acute illness, as opposed to a chronic, progressive illness such as chronic pancreatitis. The chills and a low-grade fever suggest the presence of an infectious or a highly malignant process, such as lymphoma. The absence of jaundice is helpful, since it is evidence that the patient's illness is not caused by a bile-duct stone. Moreover, acute biliary obstruction as a result of a bile-duct stone would be unusual in a young man. A patient with acute cholecystitis could present with a 10-day history of increasing abdominal pain without evidence of biliary obstruction; a patient with a liver abscess could present with subacute right upper quadrant abdominal pain and a low-grade fever. With these possibilities in mind, we can obtain additional information from the physical examination.
There was tenderness to the point of guarding and rebound tenderness in the right upper quadrant. These findings are highly suggestive of acute cholecystitis or a liver abscess. However, there was no evidence of a Murphy sign (i.e., a pause in the normal respiratory motion during inspiration and compression of the right upper quadrant). The liver did not appear to be enlarged, and there was no elevation of the right hemidiaphragm. The absence of blood in the stool argues against an active inflammatory or peptic process in the duodenum. Since there is no mention of spider angiomata, palmar erythema, or splenomegaly, chronic liver disease also seems to be an unlikely diagnosis.
The results of initial laboratory tests included a normal hematocrit but an increased white-cell count. The amylase and lipase levels were normal. The results of liver-function tests were also normal. These findings are important because they essentially rule out the possibility of acute pancreatitis, cholangitis, or a liver abscess. The normal results of the liver-function tests also make the possibility of severe acute cholecystitis very unlikely. Finally, a serologic test for H. pylori was positive, which may indicate the presence of an active infection or a previous exposure.
I shall turn to the information provided by the radiographic studies. The abdominal films show that there were no pancreatic, splenic, or liver parenchymal calcifications and no small-bowel obstruction. The CT scan obtained on the first day showed a large, complex, partially cystic mass involving the neck of the pancreas and the porta hepatis. The lesion appeared to be adjacent to the pancreas. There was no evidence of biliary obstruction, and the bile duct and gallbladder appeared to be intact and free of stones or infection. The liver was normal, and there was no evidence of cirrhosis, ascites, or an abscess. The cystic lesions were somewhat enhanced after the intravenous administration of contrast material.
Cystic Lesions of the Pancreas
Many cystic lesions of the pancreas might explain these findings. The most common cystic lesion of the pancreas is a rapid collection of fluid, which usually develops in association with acute pancreatitis.1 Acute peripancreatic fluid collections are usually well-demarcated areas adjacent to the pancreas and are composed of inflammatory debris and fluid derived from the pancreas.2 Since these fluid collections are not vascular, there is little enhancement after the administration of contrast material during CT scanning.3 In the case under discussion, the finding of a completely normal pancreas on CT scanning is further evidence that the cystic lesion in question does not represent a complication of acute pancreatitis.
Two cystic lesions of the pancreas — serous cystadenoma and islet-cell tumor of the pancreas — are enhanced after the administration of contrast material. Serous cystadenomas are most commonly microcystic, with a honeycombed appearance.4 They are benign and rarely cause symptoms. The increased vascularity of these lesions recognized on CT scanning is a result of a lush capillary network running along the walls of the cysts.5 Recently, it has been noted that nearly one third of serous cystadenomas are macrocystic and mimic mucinous cystic lesions. Only about 20 percent have the central stellate calcifications that are diagnostic of serous cystadenomas. I think that the CT appearance of the cystic lesion in the current case and the patient's clinical features on presentation make a serous cystadenoma very unlikely.
Islet-cell tumors of the pancreas may occasionally take the form of a complex cystic mass. They are very vascular and have an arterially enhancing feature that is obvious during CT scanning.6 When the tumors are cystic, rim enhancement may be visible on CT scans. The lesions may be quite heterogeneous, because of spontaneous bleeding and necrosis within the tumor. Most of them are nonfunctioning.7 However, islet-cell tumors are most commonly located in the tail of the pancreas, and they are usually solid. It would be very unusual for a patient with a cystic islet-cell tumor to present with right upper quadrant pain and rebound tenderness.
A rare cystic tumor of the pancreas is the solid cystic pseudopapillary tumor.8 This lesion appears to be a variant of a neuroendocrine tumor and usually occurs in young women.9 Many of these tumors have progesterone receptors. Although they may be very large, these tumors rarely cause symptoms. Most are not vascular and are not enhanced after the injection of contrast material.10 For these reasons, I am eliminating a solid cystic pseudopapillary tumor of the pancreas from the differential diagnosis in this case.
The last cystic lesion to be considered is a mucinous lesion, such as a mucinous cystadenoma or an intraductal papillary mucinous tumor. Mucinous cystadenomas arise from mucinous epithelium within the pancreatic parenchyma but are often associated with ovarian-type stroma adjacent to the cystic lesion.11 These lesions are commonly found in young women and rarely in young men. Furthermore, they are not classically enhanced on CT scanning.5 A malignant mucinous cystic neoplasm could have many of the features seen on this patient's CT scan.12 However, it would be unusual for a young man to present with this type of malignant lesion and with subacute abdominal pain. A pancreatic lymphoma is another possibility, since such a lesion might enhance on CT scanning and could cause severe abdominal pain and fever, but lymphomas are typically solid lesions.13
The clinicians caring for this patient chose to treat him initially with ranitidine, metronidazole, ampicillin, minidose heparin, and morphine, which was given by means of a patient-controlled analgesia device. They must have been concerned that his pain arose from a complication of H. pylori infection. The use of morphine indicates the severity of the abdominal pain and suggests the presence of an active, acute process from an infection or a rapidly expanding malignant tumor. The decision was made to obtain tissue from the lesion by fine-needle aspiration during endoscopic ultrasonography. This was a wise choice, since obtaining a biopsy specimen of the lesion during CT scanning would probably have been difficult.14
The ultrasonographic examination revealed a large, complex, heterogeneous lesion adjacent to the pancreas. The parenchyma in the head of the pancreas was abnormal, with an appearance suggestive of early chronic pancreatitis. The complex, cystic lesion was poorly defined and was not a discrete lesion within the pancreas. Instead, it appeared to be located in the peripancreatic area and extended superiorly to the porta hepatis. These findings are consistent with the possible presence of a malignant lesion, such as a lymphoma or a mucinous cystadenocarcinoma, or an inflammatory process, such as a peripancreatic fluid collection. A primary infection of the pancreas, such as cytomegalovirus pancreatitis, a bacterially infected peripancreatic fluid collection, or a granulomatous process arising from tuberculosis or infection with atypical mycobacteria, is also possible.
Infectious Processes
Bacterial, Fungal, or Viral Infection
The next clues come from the cytologic features of the aspiration specimen. The finding of acute inflammatory cells in the aspirate strongly suggests that the process is not a malignant one. The absence of intranuclear inclusions in the epithelial cells is evidence against a viral cause. Another possibility is primary bacterial or fungal infection of the pancreas. Primary fungal infections of the pancreas are rare and are usually associated with acute pancreatitis and necrosis. Candida albicans is the most common causative organism and would have been seen in the aspirate. Furthermore, it would be very unusual for a young, otherwise healthy man to have a primary candidal infection of the pancreas.15 Such an infection could be a possibility if the patient were positive for the human immunodeficiency virus (HIV). However, we know nothing about his risk factors for HIV infection, and we do not have results of HIV testing.
A repeated CT scan was performed with the use of thin slices, with attention to the pancreas. Again, a complex cystic lesion was identified in or adjacent to the pancreas. There was no evidence of vascular invasion, suggesting that this process was nonneoplastic in nature.
Mycobacterial Infection
The last type of infection we should consider is a primary mycobacterial infection of the pancreas or adjacent lymphoid tissue.16 This rare infection usually starts in the peripancreatic lymph nodes and initially spares the pancreas.17 Lesions resulting from mycobacterial infection of the pancreas are often complex and cystic, and they mimic cystic neoplasms of the pancreas.18,19 Their cystic nature and the finding of rim enhancement on CT studies probably reflect the presence of central necrosis within the infected lymph nodes.20 The absence of inflammatory changes in the mesentery and jejunum and the absence of enlargement of the liver and spleen point to infection with Mycobacterium tuberculosis rather than M. avium complex.21 Mycobacterial infection of the pancreas causes fever, pain, and abdominal tenderness.
If left untreated, mycobacterial infection of the pancreas is highly lethal, but it is responsive to antimycobacterial agents. Most cases are not diagnosed preoperatively, since special staining of biopsy specimens is necessary and since cultures of the aspirate require prolonged incubation.22 Fine-needle aspiration has been used to diagnose the presence of acid-fast bacilli in lesions of the pancreas, but only with the use of mycobacterial stains.23 Findings on examination of fine-needle aspiration samples are diagnostic in only 30 to 40 percent of cases.
In Morocco, tuberculosis is a widespread public health problem, with an annual incidence of more than 100 infections per 100,000 people.24 When immigrants from a country where the risk is high settle in developed countries, they may be responsible for outbreaks of infection. In the Netherlands, it was estimated that 17 percent of the cases of tuberculosis could be traced to infected immigrants, and among these immigrants Morocco was the second most common country of origin.24
The diagnostic procedure in this patient could have been Ziehl–Neelsen staining of the material obtained by fine-needle aspiration, which would have disclosed the presence of mycobacteria. If these stains did not reveal acid-fast bacilli, a laparotomy would have been necessary to obtain diagnostic tissue.
Dr. Nancy Lee Harris (Pathology): I would like to invite the medical students to discuss the differential diagnosis.
Adam Cohen (Harvard Medical School student): The differential diagnosis of cystic pancreatic masses includes pseudocysts, cystadenomas, and cystic malignant tumors. In a previously healthy young man with fever and spreading of the mass beyond the pancreas, we believe that none of these lesions is likely. The radiologic findings are more consistent with a mass of lymph-node origin that is adjacent to, but does not actually involve, the pancreas. The differential diagnosis of cystic lymphadenopathy includes infectious diseases, sarcoidosis, lymphoma, and rare disorders such as Whipple's disease. Given the acute onset and the inflammatory changes found on examination of the fine-needle aspiration specimen, we believe that an infectious cause is likely. Since tuberculosis is endemic in Morocco, the most likely diagnosis is abdominal abscess from M. tuberculosis infection. The diagnostic procedure could be acid-fast staining of the fine-needle aspirate for mycobacteria; it also could be subtotal pancreatectomy, removal of the abscess, and acid-fast staining of the surgical specimen.
Clinical Diagnosis
Pancreatic mass, cystic neoplasm, or abscess.
Dr. William R. Brugge's Diagnosis
Mycobacterium tuberculosis infection of the peripancreatic lymph nodes.
Pathological Discussion
Dr. Joseph Misdraji: The specimen obtained by fine-needle aspiration showed signs of acute and chronic inflammation, consistent with the presence of an abscess. Neither histiocytic multinucleated giant cells nor granulomas were seen. An acid-fast stain was not performed on that specimen because it lacked a granulomatous component, and it was not sent for microbiologic culture.
Dr. Steven Abbate performed a laparotomy. A cavitated lesion beneath the liver was unroofed as the edge of the liver was lifted, and portions of it were sent for Gram's staining and culture. The intraoperative Gram's stain was negative. Further inspection disclosed a mass, 3 cm in diameter, adherent to the superior aspect of the pancreas at the level of the neck (Figure 2). A distal pancreatectomy was performed to excise the mass. An enlarged celiac lymph node was also removed.
Figure 2. Photograph of the Gross Specimen Obtained during Distal Pancreatectomy.
The mass, 3 cm in diameter, had been located at the level of the pancreatic neck. The cut surface is mottled white, tan, and brown and contains cystic areas lined by tan, granular, necrotic-appearing tissue.
The cut surface of the mass was mottled white, tan, and brown and contained several necrotic, cystic areas. On histologic examination, the mass was found to consist of matted lymph nodes with numerous granulomas, many of which contained central caseous necrosis (Figure 3). Areas of extensive necrosis surrounded by palisading histiocytes were also present. The inflammatory process extended a short distance into the pancreas. Despite multiple attempts, we were unable to identify organisms on acid-fast stains or silver stains. A diagnosis of necrotizing granulomatous lymphadenitis involving the peripancreatic and celiac lymph nodes was made. The celiac lymph node also contained necrotizing granulomas. Subsequently, cultures yielded M. tuberculosis complex. Therefore, the final pathological diagnosis was tuberculous lymphadenitis involving the peripancreatic lymph nodes, with associated chronic pancreatitis.
Figure 3. Photomicrographs of the Specimen Obtained during Distal Pancreatectomy (Hematoxylin and Eosin).
Microscopical examination shows that the mass consists of matted lymph nodes with granulomatous lymphadenitis (Panel A, x100); in areas (right), the granulomas coalesce. Many of the granulomas contain amorphous, eosinophilic, granular debris, indicating caseation necrosis (Panel B, x200). Panel C (x200) shows the edge of a large necrotic zone (top right) that is lined by palisading histiocytes. Panel D (x100) shows that the inflammatory process extends from the peripancreatic lymph nodes (right) into the pancreas (left) and is characterized by inflammation, fibrosis, and acinar atrophy. A residual islet of Langerhans is present (top left).
Some of the reported cases of pancreatic tuberculosis may actually represent cases of tuberculosis in the peripancreatic lymph nodes, as in this case. Tuberculosis can affect the pancreas either by contiguous spread from the peripancreatic lymph nodes or by hematogenous spread.25 Patients with pancreatic tuberculosis most often present with a pancreatic mass mimicking a carcinoma,25 although they may also present with acute pancreatitis, a chronic pancreatic abscess, obstructive jaundice, or gastrointestinal bleeding.26,27,28,29,30
Pancreatic tuberculosis is rare, even in countries where tuberculosis is endemic. Most often, it occurs in the setting of miliary tuberculosis. In two large studies, the incidence of pancreatic tuberculosis in patients with miliary tuberculosis was 2.1 percent and 4.7 percent.31,32 Pancreatic tuberculosis without involvement of other sites is exceptionally rare; fewer than 30 cases have been reported.
The rarity of pancreatic tuberculosis may be due to the fact that the pancreas appears to be somewhat resistant to M. tuberculosis infection. Intrapancreatic injections of M. tuberculosis cause pancreatic lesions only when large inocula are used. Several investigators have shown that pancreatic extracts and purified lipases and DNAses have antimycobacterial properties.33
Dr. Harris: Dr. Kotton, you saw the patient after the operation. Will you tell us about his treatment and subsequent course?
Dr. Camille N. Kotton (Infectious Disease): When my colleagues and I saw the patient, he had recovered from the operation and had been discharged, but he later returned to the hospital because of persistent low-grade fevers. Because of the pathologic findings of granulomas, we were very concerned about tuberculosis, although the culture results were still pending. Additional serologic tests for antibodies to HIV types 1 and 2, brucella, schistosoma, and echinococcus were all negative. Ruling out these infections was helpful, given the rarity of tuberculosis of the pancreas. We believed this patient probably had tuberculosis, and we initiated a four-drug regimen. Once his cultures grew M. tuberculosis and the isolate was found to be pan-sensitive, we reduced the four-drug regimen to a two-drug regimen. He was treated with that regimen for six months and tolerated it well.
Dr. Harris: Is the disease in this case a manifestation of primary gastrointestinal tuberculosis, a primary infection of lymph nodes surrounding the gut, or reactivation of old disease with hematogenous spread to the upper abdominal lymph nodes?
Dr. Kotton: I would assume that it is a reactivation of tuberculosis acquired while the patient was living in Morocco. On further questioning, he told us his brother had had active tuberculosis at some point during his childhood. It is not known why his disease reactivated at this time.
Anatomical Diagnosis
Tuberculous lymphadenitis involving the peripancreatic lymph nodes.
Addendum
One year after completing antituberculosis therapy, the patient was in good health, and no further lesions were seen on repeated abdominal CT scanning.
Source Information
From the Gastroenterology Unit, Department of Medicine (W.R.B.), and the Departments of Radiology (P.R.M.) and Pathology (J.M.), Massachusetts General Hospital; and the Departments of Medicine (W.R.B.), Radiology (P.R.M.), and Pathology (J.M.), Harvard Medical School.
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