Jean Schultz described a case of pancreatic-gland-like tissue at the base of the ileal diverticulum in 1727, which is commonly believed to be the first case of ectopic pancreas recorded in literature. The lesion has since been reported in various parts of the human body, but the true incidence of ectopic pancreas remains undetermined as most cases are asymptomatic. Existing data indicates a prevalence of 0.2% at laparotomy and 0.55% to 13.7% on autopsies as mentioned before.[2,3]
Most of the lesions were found in the upper gastrointestinal tract and proximal jejunum, while lesions in the ileum were relatively rare, and when seen, they were usually associated with Meckel diverticulum. Pearson reviewed 589 cases of ectopic pancreas and found that only 3% of the lesions were located in the ileum and 6% in Meckel diverticulum. Another large sample study of 212 cases conducted by Dolan RV found only 3 cases (1.4%) in the ileum wall and 11 cases (5.2%) in Meckel diverticulum. The data from our hospital revealed only 5 cases (2.9%) in the ileum wall and 5 cases in Meckel diverticulum out of a total of 171 ectopic pancreatic cases in recent 9 years. However, a retrospective study by Chen revealed a 12.8% proportion of ectopic pancreas in the ileum wall and a 7.7% proportion of ectopic pancreas in Meckel diverticulum, which is a surprisingly high incidence. 
Studies focused on ectopic pancreas in the ileum including Meckel diverticulum are few. Traditionally, most of the lesions were considered asymptomatic and therefore clinically insignificant, and diagnoses were mainly made during abdominal radiological examinations or surgical explorations motivated by other diseases.[10,17,18] According to Armstrong, approximately half of the cases of small intestinal ectopic pancreas are asymptomatic. Some researchers even claim that ectopic pancreas in the ileum is almost always asymptomatic. When symptoms do occur, abdominal pain and gastrointestinal bleeding are most common. On the contrary, based on the limited number of case reports and several literature reviews we found, ectopic pancreatic tissues in the ileum can be quite symptomatic and may cause severe clinical manifestations and complications. According to a literature review by Kilius, most cases (5 of 7) represent ectopic pancreas in Meckel diverticulum with gastrointestinal bleeding. Abdominal pain and gastrointestinal bleeding were also frequently seen in case reports of ectopic pancreas in the ileum wall, often along with ulceration or intussusception.[11,18,20,23–25] In our study, the majority of the lesions found in clinical practice present with abdominal pain, gastrointestinal bleeding and anemia, and lesions in the ileum wall can often present as ileoileal intussusception, which is consistent with previous studies.
Generally, ectopic pancreas related symptoms can be divided into 2 categories: those possible in any mass, and those specific to pancreatic tissue. The former ones, which are mainly comprised of bowel or biliary obstruction, intussusception, and ulceration, are largely determined by the size and location of the masses. Pancreatic-tissue-specific complications are mostly pancreatitis and pancreatic neoplasm, which includes adenocarcinoma, neuroendocrine tumor, intraductal papillary mucinous neoplasm, etc. And as in the normal pancreas, ectopic pancreatitis is far more common than ectopic pancreatic neoplasm. Besides, the pancreatic juice secreted by the ectopic pancreatic tissue also may cause abdominal pain, bleeding, or perforation due to its corrosive effect. In clinical practice, however, affirmative pancreatic-tissue-specific complications are very rare, found only in a few case reports; most of the symptoms and complications are caused by the mass effect of the lesion instead. In our cases, no inflammation or neoplasm of the ectopic lesion was observed, except for a very slight lymphocyte infiltration in case 1 and a slight neutrophil infiltration in case 7.
The symptoms of the 5 cases with intussusception in our series are clearly caused by the mass effect. We believe that the bleeding in most intussusception cases was not directly from the ectopic pancreatic lesions, but from the invaginated intestine instead. The incidence of a localized pathological lead point for intussusception varies from 2% to 10%, while most cases of intussusception are idiopathic.[20,28] Several conditions, such as polyps, leiomyomas, hamartomas, neurofibromas, adenomas, inflammatory fibrous polyps, tuberculosis, lipomas, Meckel diverticulum, adhesions, and ectopic pancreas, have been reported as the lead point for intussusception. Intussusception secondary to isolated ectopic pancreas in the ileum, even though extremely rare, has been reported in multiple studies.[11,14,18,25,29] The vast majority of these reported cases occurred in children or infants, which is in line with the well-known fact that intussusceptions primarily happen in pediatric cases with only 5% of intussusceptions occur in adults. However, unlike the pediatric situations, merely 10% of intussusceptions are idiopathic in adults, and in the small intestine, they are almost always associated with benign masses. Of all the 10 patients reviewed in our study, patient age ranged from 17 to 72 years with an average of 40 years. This may be mainly due to the fact that our hospital rarely treats pediatric patients.
The pathophysiological mechanisms of symptomatic cases in Meckel diverticulum are difficult to determine. It may due to inflammation, diverticulitis, or ulcerations caused by alkaline secretions of ectopic pancreatic tissue. However, it is still hard to tell whether the bleeding was ectopic-pancreas-related or not for certain in our cases. About half of resected Meckel diverticulum contain ectopic tissues, and gastric heterotopia is the most common, reported in 23% to 50% of the cases, while ectopic pancreatic tissue is found in 5% to 16% of the cases. The main cause of bleeding from Meckel diverticulum is considered to be the acid secretion from the ectopic gastric mucosa, which then leads to ulceration and hemorrhage. However, no ectopic gastric mucosa was found in our series; therefore, 99mTc-Pertechnetate imaging made no positive discovery. Some scholars proposed that the main clinical presentation of Meckel diverticulum with ectopic pancreatic tissue is intussusception, in which case the lesions are usually located in the distal end of the diverticulum and serve as a lead point. A number of case reports backed the proposal.[33,34] Indeed, Meckel diverticulum is considered the most common pathologic lesion that acts as a lead point for intussusception. Nevertheless, more reports of symptomatic Meckel diverticulum with ectopic pancreatic tissue are intussusception-free, which are congruent with our study.[12,22,35] In fact, Meckel diverticulum without pancreas ectopia can cause similar symptoms too, so it is possible that the bleeding was not related to the ectopic pancreas lesions.
There is no reliable laboratory marker for the existence of ectopic pancreatic tissue.[10,36,37] When ectopic pancreatitis or ectopic pancreatic neoplasm occurs, which is very unusual, there may be a corresponding elevation in amylase level or tumor markers. But the elevation is usually quite mild, owing to the small size of the lesion.[38,39] Unfortunately, no assay of serum amylase level was made in our series. When gastrointestinal bleeding occurs, a decrease in hemoglobin levels can be detected. The hemoglobin level is very helpful to estimate the severity of the condition and may serve as an indicator for the necessity and urgency of surgery and other treatments such as blood transfusion. C-reactive protein and full blood count may be useful to provide information about the inflammation.
Computed tomography (CT) is one of the most important imageological examinations of small bowel diseases, and it has been extensively reported for evaluation of ectopic pancreas. Typically, CT images of ectopic pancreas in the gastrointestinal tract show a round or oval intramural soft tissue mass with smooth or microlobulated margins. The attenuation and enhancement features of the lesion reflect its microscopic composition: ectopic tissue that is predominantly composed of acini shows homogeneous avid enhancement that is greater than or equal to that of the orthotopic pancreas; hypoenhancing lesions are dominated by ductal structures and sometimes surrounded by hypertrophied muscle. A central umbilication, which fills with contrast, is a diagnostic feature thought to represent a rudimentary duct, but this feature is only found in a minority of cases. With all these characteristics theoretically summarized, it is still very difficult to make the diagnosis of ectopic pancreas effectively based on CT examination in clinical practice. Unfortunately, there is currently a lack of ideal imageological examination for the effective diagnosis of the ectopic pancreas in the ileum. However, just as this study as well as other studies demonstrated, CT is actually very effective in diagnosing intussusception with a high sensitivity, and it was considered the most useful examination for diagnosing intussusception, even though the ectopic pancreatic lesions that acted as a lead point were misdiagnosed as lipoma preoperatively in our series.[39,40] On the contrary, Meckel diverticulum, especially the ones smaller than 3 cm, may be difficult to distinguish from normal small bowel loops on CT. Typically, it appears as a blind-ending gas or fluid-filled structure that may also contain foreign bodies or enteroliths, and the neoplasms within a Meckel diverticulum, which is quite rare, can appear as a sessile or lobulated mass that often enhances with contrast and may infiltrate and thicken the adjacent intestinal wall. In our series, our radiologists were unable to identify Meckel diverticulum on CT preoperatively, and the diverticulum remained elusive under postoperative review. Still, CT plays an important role in the diagnosis and differential diagnosis of Meckel diverticulum and Meckel diverticulum-related complications.[41,42] Modern multi-detector CT, which offers improved spatial resolution and image reconstruction in coronal and sagittal planes, may help raise the efficacy.
The use of capsule endoscopy or double-balloon enteroscopy for detecting ectopic pancreas in the ileum is seldom reported in literature. Huan-Lin Chen presented a case of ectopic pancreas in the ileum identified by capsule endoscopy in 2007, and we have not found any other similar report in English literature. They performed capsule endoscopy for a patient who had noted intermittent dark bloody stool for 2 months, and the examination revealed a red polyp with a stalk located in the ileum, while other examinations like abdominal CT and small intestinal barium X-ray failed to provide any ponderable clue. In our patients, capsule endoscopy revealed anomalies in half of the cases (3 of 6 cases). In fact, capsule endoscopy is currently widely used for detecting the bleeding source in patients with obscure gastrointestinal bleeding and is proved to have high sensitivity and specificity. Of course, being unable to perform biopsy and more clear observation, capsule endoscopy cannot bear accurate preoperative diagnosis, but it still provides valuable information for better management of the disease. Despite our effort, we found only 2 case reports on the use of double-balloon enteroscopy for detecting ectopic pancreas in the small bowel, and both lesions were in the jejunum.[44,45] Ectopic pancreas found under double-balloon enteroscopy was extremely uncommon indeed. The use of double-balloon enteroscopy for the diagnosis of Meckel diverticulum, however, was widely reported, and it was considered a safe, effective, and reliable method for diagnosis before surgery.[46,47] In our cases, we found a diverticulum by double-balloon enteroscopy in the lower ileum, but the diverticulum is too deep and we were unable to make further in-depth observation. Generally, double-balloon enteroscopy was suggested to be used complementarily to other less invasive examinations including capsule endoscopy and CT when needed to confirm or establish the diagnosis.
Indubitably, symptomatic cases of ectopic pancreas in the ileum should be treated aggressively.[48,49] Segmental small bowel resection and reduction of intussusception (if found) are the treatments of choice. Diverticulectomy can be adopted if the lesion is found inside a diverticulum and the adjacent bowel is intact. The management of asymptomatic cases is still under debate.[48,49] Some argue that all cases of ectopic pancreas, symptomatic or not, should be treated, but others claim that conservative management should be adopted for asymptomatic cases. In our opinion, segmental small bowel resection or diverticulectomy should be performed for large lesions and lesions inside the diverticulum, while small asymptomatic lesions in the ileum wall can be surgically treated or not. The surgical treatment is safe and effective in most cases.
There are several limitations of this study. First, this study is a retrospective study, and some data were not well recorded or preserved. Second, only a small number of patients were enrolled. Thirdly, we only described the histopathological features of the ectopic pancreas lesions instead of the whole resected parts. Finally, we are unable to clarify the pathophysiological mechanisms of symptomatic cases in Meckel diverticulum.
In summary, ileac ectopic pancreas can be seen in the ileum wall or Meckel diverticulum. The majority of the lesions found in clinical practice present with abdominal pain, gastrointestinal bleeding, and anemia. Lesions in the ileum wall can often present as ileoileal intussusception. CT, capsule endoscopy, and double-balloon enteroscopy can be helpful as preoperative examinations, but despite these advanced diagnostic tools, the preoperative diagnosis of an ectopic pancreas remains challenging, and the final diagnosis still depends on the postoperative histological examination. Segmental small bowel resection and reduction of intussusception (if found) are the treatments of choice.
Conceptualization: Saiheng Xiang, Guoqiang Xu.
Data curation: Saiheng Xiang.
Formal analysis: Saiheng Xiang.
Investigation: Saiheng Xiang, Fenming Zhang.
Methodology: Saiheng Xiang, Guoqiang Xu.
Project administration: Guoqiang Xu.
Resources: Saiheng Xiang.
Supervision: Guoqiang Xu.
Validation: Saiheng Xiang, Fenming Zhang, Guoqiang Xu.
Visualization: Saiheng Xiang.
Writing – original draft: Saiheng Xiang.
Writing – review & editing: Saiheng Xiang, Fenming Zhang, Guoqiang Xu.
Guoqiang Xu orcid: 0000-0003-1337-9120.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
ectopic pancreas; gastrointestinal bleeding; ileum; intussusception; Meckel diverticulum