Lesions of the Pancreas Flashcards
Discuss disorders of the pancreas in the pediatric population.
Disorders of the pancreas can origin from congenital structural abnormalities such as annular pancreas, pancreas divisum and pancreaticobiliary malunion and may require surgical interventions.
Congenital hyperinsulinism (CHI) is a rare and complex genetic disorder, that can present with a focal, diffuse or atypical lesion.
Near-total pancreatectomy is the procedure of choice for diffuse CHI, whereas a localized resection is curative for focal CHI.
An increasing incidence of pancreatitis in children has been reported recently—likely due to the increased incidence of obesity, drug associated pancreatitis and improvements in detection.
Benign and malignant pancreatic tumors are relatively uncommon in children, thus making diagnosis, classification and management challenging.
What are the surgical conditions affecting the pancreas in infants and children?
– congenital anomalies
– inflammatory conditions
– neoplasms
– trauma (see Chap. 56 on abdominal trauma)
What are the most common congenital anomalies of the pancreas?
Annular pancreas: caused by incomplete migration of the ventral pancreatic anlage (annular part encircles the second portion of the duodenum and drains independently into the duodenum or into Wirsung’s duct); associated with Down’s syn- drome, malrotation, intrinsic duodenal obstruction, esophageal atresia and heart defects; duodenal obstruction should be bypassed by performing duodenoduodenostomy or duodeno-jejunostomy without resecting the pancreatic tissue.
Pancreas divisum: pancreatic buds are not fused and the two ducts are separate with majority of the pancreatic secretions draining from the minor papilla; most patients are asymptomatic; stenosis of the minor papilla may lead to recurrent acute pancreatitis and may be treated with sphincteroplasty.
Pancreaticobiliary malunion: common channel between the pancreatic and bil- iary ducts above the duodenal wall; this anatomy is common in choledochal cysts; channel may become clogged with stones or plugs causing obstruction and dila- tion, resulting in pancreatitis and sometimes jaundice.
Congenital hyperinsulinism (CHI): inappropriate insulin secretion by the pan- creatic β-cells secondary to various genetic disorders; recurrent episodes of hyper- insulinemic hypoglycemia imply high risk of brain damage.
What is the incidence of CHI?
CHI is most frequent cause of persistent hypoglycemia in neonates and infants; estimated incidence is 1 in 50.000 live births, but can be as frequent as 1 in 500 in countries with high rate of consanguinity.
What are the different histological forms of CHI?
Focal CHI: consists of focus of adenomatous islet cell hyperplasia surrounded by normal pancreatic tissue; focal lesions vary in size from a few millimeters to greater than a centimeter or more; can be located in the surface of the pancreas or deep within the organ.
Diffuse CHI: primary histological hallmark feature is beta cell nucleomegaly; in the vast majority of cases abnormal beta cells are distributed homogeneously throughout the pancreas.
In addition to the two major forms, there are rare atypical histological cases of CHI that are neither focal nor diffuse.
How is CHI diagnosed?
Valuable diagnostic information is obtained from a blood sample drawn during hypoglycemia:
• Fasting and/or post-prandial hypoglycemia (<2.5–3 mmol/L)
• abnormal detectable amounts of insulin and inappropriately low levels of free fatty acids and ketones
• high requirement for intravenous glucose to maintain adequate glucose lev-
els (>8–10 mg/kg/min)
41 Pancreas 289
• rise of the glucose level after injection of glucagon.
• genetic test for variants related to focal or diffuse CHI (see below)
• PET scan using 18F-DOPA (see below).
What techniques are used to determine whether the patient has focal or diffuse CHI, and how can focal lesions be localized?
Combination of genetic testing and/or imaging studies are needed to determine if patient has focal or diffuse CHI:
When genetic testing confirms diffuse CHI (one mutation on the maternal allele plus one mutation on the paternal allele)—no imaging studies are necessary;
When genetic testing is suggestive of focal CHI, a 18F-DOPA PET/CT scan must be done to confirm the diagnosis of focal CHI and localize the lesion.
What are the most common presenting symptoms of CHI?
Neonates present with poor feeding, perioral cyanosis, lethargy, hypotonia, irritability and seizures.
Unfortunately, untreated neonates can develop neurological abnormalities due to hypoglycemia.
Older patients can present with typical clinical features of hypoglycemia like pallor, sweat and tachycardia.
What strategies are used for the medical treatment of CHI?
Hypoglycemia must be rapidly treated to prevent irreversible brain damage (glucose load and/or a glucagon injection), followed by treatment to prevent recurrence of hypoglycemia (frequent and glucose-enriched feeding, diazoxide, nifedip- ine and octreotide).
Describe the surgical treatment of focal and diffuse CHI?
Focal CHI: localized resection of the focal lesion is curative;
Head or neck focal lesions: open resection of the lesion with small rim of surrounding normal pancreatic tissue and pancreatico-jejunostomy to allow drainage of the distal pancreas.
Distal focal lesions: distal pancreatectomy (open or laparoscopically).
Diffuse CHI: open or laparoscopic near-total pancreatectomy (95%) is con- sidered as gold standard; (tail, body, uncinate process and part of pancreatic head are resected, leaving a rim of pancreatic tissue surrounding the common bile duct and along the duodenum); long-term outcome is characterized by a high risk of diabetes [1].
What are the causes and findings of acute pancreatitis in children?
Most common causes: trauma, choledocholithiasis, congenital structural abnor- malities of pancreatic and/or biliary system (choledochal cyst), systemic illness, drugs, familial or idiopathic.
Clinical findings: abdominal pain, vomiting, jaundice, fever, diarrhea, back pain, irritability and lethargy; in severe cases: shock, multiorgan failure including dyspnea, oliguria, hemorrhage and mental status change
Laboratory findings: elevated amylase and lipase are commonly found, but normal values do not rule out pancreatitis.
Radiographic findings:
Plain abdominal X-ray: paralytic ileus, colon cut-off sign, sentinel loop sign, cal- cified gallstones or pancreatic stones;
Plain chest X-ray: pleural effusion, ARDS, pneumonia
Abdominal ultrasound (US): pancreatic abnormalities, inflammation, free fluid, pseudocysts, dilated biliary or pancreatic ducts, gallstones
Abdominal computer tomography (CT) (95% sensitivity): pancreatic enlargement/ mass/trauma, fluid collections, necrosis, hemorrhage
Magnetic resonance cholangiopancreatography (MRCP): delineating ductal anatomy
How is acute pancreatitis treated in children?
Medical treatment: mainly supportive with fluid and electrolyte supplementation,
enteral feeding and analgesia [2]; antibiotic prophylaxis is not recommended [3].
Surgical treatment:
Infected pancreatic necrosis: extensive drainage for source control; in case of insufficient response—open surgical debridement or necrosectomy is rarely performed.
Symptomatic pseudocysts: drainage procedure after a cyst wall has formed (4–6 weeks); done by endoscopic drainage or surgical cystgastrostomy, cystduo- denostomy, or cystjejunostomy (open or laparoscopic)
If drainage is needed prior to maturation of the cyst wall: external drainage (open or percutaneously) may be required; complications: fistula formation and recurrences.
Ductal obstruction: endoscopic retrograde cholangiopancreatography (ERCP) for clearance of stones, or stenting of ductal disruption.
ERCP with sphincterotomy for stricture at the ampulla to allow improved pancreatic fluid drainage.
How is chronic pancreatitis defined?
Irreversible structural damage to the pancreas with or without exocrine and endocrine insufficiency; may be the result of acute recurrent pancreatitis.
How does chronic pancreatitis present in children?
Presenting symptoms: recurrent or persistent abdominal pain associated with nausea, vomiting, anorexia, weight loss and malnutrition; pancreatic endocrine insufficiency may lead to diabetes; pancreatic exocrine insufficiency may lead to maldigestion with diarrhea, steatorrhea, gas bloating, intermittent abdominal dis- tention and vitamin deficiency (AEDK) [4].
What are the appropriate imaging studies in a child with chronic
pancreatitis?
US: inflammation, fluid collections, pseudocysts, gallstones
CT: pancreatic atrophy, dilated pancreatic ducts, calcifications, masses, fluid collections, necrosis and hemorrhage, guidance of interventions (drain placement or vessel embolization)
MRCP: delineating ductal anatomy and evaluating for strictures, stones, tumors and ductal anomalies.
ERCP: stone removal, stricture dilation or stenting, stricture or mass biopsy, sphincterotomy
Endoscopic ultrasound: pancreas visualization, biopsies of the mucosa, masses, strictures, lymph nodes, pseudocyst aspiration or drainage.
How is chronic pancreatitis treated?
Medical treatment:
Endocrine insufficiency: monitoring and treatment for diabetes
Exocrine insufficiency: supplementation of pancreatic enzymes, antacids, fat solu- ble vitamins (AEDK)
Surgical treatment: Indications:
– failure of medical and endoscopic management of chronic pain
– complications such as pseudocysts, strictures or obstructing stones.
Pseudocysts: see surgical treatment of acute pancreatitis
Obstructions and strictures: ERCP to clear stones, protein plugs or to stent a ductal disruption; endoscopic or open sphincterotomy for stricture of the ampulla Stenotic sphincter: sphincteroplasty
Multiple ductal strictures: side-to-side longitudinal pancreatico-jejunostomy
(Puestow procedure)
“Head-dominant” disease: combination of Puestow procedure with partial
resection of pancreas head in case of duct dilation;
pancreaticoduodenectomy (Whipple procedure) in case of non-dilated pancreatic duct
“Tail-dominant” disease: distal pancreatectomy.
How can pancreatic tumors be classified?
Pancreatic tumors can be classified as malignant or benign, cystic or solid and of exocrine versus endocrine origin [5].
PRIMARY
1) Exocrine
Benign:
serous cystadenoma (microcystic/oligocystic), mucinous cystadenoma, mature cystic teratoma
Borderline malignant: solid pseudopapillary neoplasm (SPN; previously known as Frantz tumor)
Malignant: pancreatoblastoma mucinous cystadenocarcinoma acinar cell carcinoma pancreatic ductal adenocarcinoma
2) Endocrine Benign: insulinoma sporadic gastrinoma VIPomas
Borderline to frankly malignant:
multiple endocrine neoplasia (MEN) associated insulinoma and gastrinoma
NON-EPITHELIAL PANCREATIC TUMORS
What is the most common pancreatic tumor in children?
Solid pseudopapillary tumor of the pancreas: most commonly affects older adolescent females; tumor has both, cyst-like and solid parts; tumor is unlikely to spread;
Very good prognosis.
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The most common pancreatic tumor in all recent pediatric series is solid pseudopapillary tumor (SPT), an exocrine tumor reported in approximately two-thirds of all children with pancreatic neoplasms.
It is also known as Frantz tumor.
The tumor is typically found in adolescent females, but can present in younger patients.
Asian patients are at an increased risk.
Presentation with jaundice is rare, as there is a predilection for the body and tail of the pancreas.
The most common symptoms are vague abdominal pain, early satiety, and an indolent, slow-growing mass.
It is not uncommon for the tumor to reach very large sizes prior to diagnosis.
The tumor has a typical appearance of a heterogeneous solid mass with central areas of necrosis on CT or MRI. Calcifications may be seen.
It has no tumor markers.
SPT is considered a tumor with low malignant potential.
Resection with negative margins constitutes sufficient therapy.
Long-term survival is excellent, approaching 95%, even with positive margins.
Figure 57.9 shows a typical SPT in a 14-year-old girl of Chinese origin who presented with a left abdominal mass slowly growing over several years. At operation, the tumor was completely adherent to the splenic vein. A spleen-preserving distal pancreatectomy was attempted unsuccessfully. En bloc resection of the distal pancreas and spleen was completed.
Pathology demonstrated typical features of SPT, as shown in Figure 57.10. The tumor was well-circumscribed and showed extensive necrosis and hemorrhage. Microscopically, the tumor demonstrated classic histologic features of solid pseudopapillary neoplasm. Areas of solid tumor alternated with areas of cystic degeneration in which residual tumor cells formed cuffs around blood vessels, forming “pseudopapillae.” The epithelial cells were relatively uniform with occasional nuclear grooves and periodic acid–Schiff (PAS) + hyaline globules. Foamy macrophages and cholesterol clefts were present in the areas of cystic degeneration.
Although the uniformity of the cell population is reminiscent of pancreatic neuroendocrine tumor, the low power architecture, nuclear grooves, and hyaline globules usually allow discrimination between these tumors.
Immunohistochemistry can also help to differentiate between pancreatic neoplasms.
Solid pseudopapillary neoplasms are positive for beta-catenin (most tumors harbor mutations of beta-catenin), CD56, CD10, progesterone, and cyclin D1 and may show synaptophysin and S100 positivity in certain cases.
Malignancy is extremely rare in pediatric SPTs, but the presence of cellular atypia, high proliferative index, frank necrosis without fibrovascular stroma, perineural involvement, and vascular invasion are considered poor prognostic factors that should prompt investigation for lymph node and metastatic involvement.
Sherif
Which tumor is associated with Beckwith-Wiedemann and familial adenomatous polyposis (FAP)?
Pancreatoblastoma: usually occurs in children aged 10 years or younger; tumor may produce adrenocorticotropic hormone (ACTH) and antidiuretic hormone (ADH); may spread to the liver, lungs, and lymph nodes; good prognosis
Which tumors are associated with MEN1 syndrome?
Islet cell tumors: rare in children; can be benign or malignant; most common types: insulinomas and gastrinomas.
What are the presenting symptoms of pancreatic tumors in children?
Most pancreatic tumors are slowly growing with few specific symptoms in the early phases: epigastric abdominal pain, palpable abdominal mass, jaundice, pruritus
Rarely severe abdominal pain or acute abdomen due to acute hemorrhage into tumor or tumor rupture
Endocrinologically active tumors (insulinoma/gastrinoma): signs and symptoms related to the effects of the hypersecretion of the active hormone.
What are the most useful diagnostic studies for pancreatic tumors in children?
Transabdominal ultrasonography: first choice, accurate in the initial delineation of most pancreatic lesions.
Magnetic resonance imaging (MRI) (gold standard): advantage of providing very precise anatomic differentiation between the various tissues; multiplanar capabilities
Abdominal CT: provides precise multiplanar information; many tumors have characteristic appearance on CT.
Endoscopic ultrasound: visualization of very small lesions (too small to be seen adequately on CT/MRI); fine needle aspiration or biopsy
How are tumors of the pancreas treated in children?
Treatment of pancreatic tumors is individualized.
In general, operative exploration is mandated to obtain tissue diagnosis and to determine resectability.
Benign tumors
Benign lesions of exocrine pancreas: resection
Endocrine tumors of the pancreas (malignant or benign)
Functional lesions should be treated by enucleation from the pancreatic head and body or distal pancreatic resection of the tail; additional peri-pancreatic lymph node resection (to avoid small deposits of tumor cells, that can continue to pro- duce active hormones); additional duodenotomy for hormonally active lesions in the submucosa of the duodenum [6].
Malignant tumors: resection—even in the presence of local invasion; Long-term survival is expected for solid and cystic tumors of the pancreas, which metastasize infrequently and represent the most common histologic variant in children. Distal lesion (body and tail of pancreas) are treated by distal pancreatectomy. Tumors in head and neck can be enucleated with duodenal preserving operation followed by pancreatico-jejunostomy. Alternatively, a Whipple procedure (pancre- atico-duodenectomy with removal of the head of the pancreas, duodenum, portion of the common bile duct, gallbladder, ±part of the stomach) is required [6].
What is the embryology of the pancreas?
The pancreas originates during week 4 of gestation as dual evaginations from the foregut endoderm.
The dorsal pancreatic bud gives rise to the body and tail of the pancreas, its minor duct (Santorini) and papilla, and the continuation of the major duct (Wirsung) into the body and tail.
The ventral pancreatic bud arises from the biliary diverticulum and swings around the dorsal aspect of the duodenal anlage during gut rotation to give rise to the head of the pancreas as well as the proximal portion of the Wirsung duct.
The two pancreatic buds fuse to form one pancreas at approximately 7 weeks’ gestation, although it appears that complete fusion of the two ducts to form the main pancreatic duct is delayed until the perinatal period.
The endocrine component of the pancreas, the islets of Langerhans, starts to differentiate before evagination of the pancreatic buds from the wall of the foregut.
The islets comprise 10% of the pancreas during early embryonic and fetal life, but this contribution decreases to less than 1% in adulthood.
Pancreatic acini begin to form at 12 weeks’ gestation and begin to accumulate organelles and zymogen granules at this stage, but they do not secrete appreciable amounts of enzyme until birth.
The pancreas is retroperitoneal and is light pink in children. The acini can be seen under low-power loupe magnification, as can the septa dividing the lobulations.
The head of the pancreas lies in the C-loop of the duodenum while the uncinate process, emanating from the posteromedial portion of the head, projects under the superior mesenteric artery (SMA) and vein.
The neck of the pancreas is defined as that portion of the pancreas anterior to these vessels.
The body and tail, to the left of these vessels, angle sharply toward the hilum of the spleen.
The main pancreatic duct courses along the posterior aspect of the gland and curves downward in the head to run alongside the common bile duct, which runs either in a groove posterior to the pancreas or within the substance of the posterior gland.
The main pancreatic duct and common bile duct may fuse to form a common channel before entry into the duodenum.
The pancreas is convex, and its midportion is reflected over the anterior surface of the upper lumbar vertebrae and aorta. Its lateral aspects fall posteriorly toward each kidney.
The arterial supply of the pancreas is from the celiac and SMA arteries, which form the pancreaticoduodenal arcade. The pancreas also has anastomoses from the splenic artery.
What is pancreas divisum?
Pancreas divisum is an anomaly of the pancreas present in 10% of the population and is thought to result from failure of the dorsal duct to fuse with the ventral duct.
It is the most common congenital anomaly of the pancreas.
In pancreas divisum, the majority of exocrine pancreatic secretions, including those from the entire body and tail, must drain through the small minor duct of Santorini.
Endoscopic retrograde cholangiopancreatography (ERCP) is regarded as the most definitive and reliable diagnostic method for revealing pancreas divisum.
However, the ERCP sometimes can induce pancreatitis.
Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive and accurate method in the diagnosis of pancreas divisum.
The clinical relevance of pancreas divisum remains controversial.
A relative obstruction to pancreatic exocrine secretory flow through the duct of Santorini and minor papilla could result in pancreatitis in a small number of patients with pancreas divisum.
What are ectopic pancreatic rests?
Ectopic pancreatic rests are frequently encountered along foregut derivatives such as stomach, duodenum, jejunum, and colon, but are also infrequently encountered in the thorax and other sites.
These lesions are found in approximately 2% of autopsy series and represent the most common anomaly of the gastric antrum.
Moreover, they may cause gastric outlet obstruction.
Their origin is unknown, but may be the result of aberrant epithelial–mesenchymal interactions that lead to the transdifferentiation of embryonic epithelium into pancreatic epithelium.
Several studies have implicated defects in hedgehog signaling and Notch signaling as the cause of ectopic pancreatic rests.
Ectopic rests are typically asymptomatic and are encountered incidentally at laparotomy or during endoscopy.
They can be identified as pancreatic tissue visually, because the surface has the same granular acinar appearance as the normal pancreas.
These ectopic pancreatic rests usually do not become inflamed, possibly because they contain numerous small drainage ducts that usually do not obstruct; however, they can occasionally cause intestinal obstruction or bleeding.
When encountered at laparotomy, ectopic rests should probably be excised, unless the excision would entail significant risk of complications.
What is an annular pancreas?
An annular pancreas is thought to result from faulty rotation of the ventral pancreatic bud in its course around the posterior aspect of the duodenal anlage.
The duodenum is encircled and can be obstructed by normal pancreatic tissue.
Abnormal expression patterns of endodermal hedgehog may be responsible for the formation of annular and ectopic pancreas.
Duodenal atresia and stenosis, intestinal malrotation, and trisomy 21 often can be found in combination with an annular pancreas.
The clinical significance relates primarily to an intrinsic duodenal obstruction, typically with bilious vomiting.
Radiographic studies may reveal the classic finding of the “double-bubble” sign.
Management consists of bypass of the obstructing lesion with a duodenoduodenostomy or gastrojejunostomy, depending on the anatomy.
Resection or division of the annular pancreas should not be performed due to the variable and complex ductal drainage system.
Occasionally, patients with complex ductal anatomy may require reoperation for pancreatobiliary anomalies not apparent at the time of the initial operation.
What is cystic fibrosis?
Cystic fibrosis (CF) is an autosomal recessive condition, seen primarily in Caucasians, and occurs in about 1 of 2500 births.
It is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes a protein expressed on the apical membrane of exocrine epithelial cells.
CF leads to significant pancreatic insufficiency.
The pancreatic secretions generally have a reduced amount of bicarbonate, a lower pH, and a lower overall fluid volume.
The inspissated secretions lead to blockage of the ducts with dilatation. This may lead to acinar cell degeneration, acute and chronic pancreatitis, and pancreatic fibrosis.
The result is impaired digestion of fats and proteins from loss of these digestive enzymes.
What are the causes of acute pancreatitis?
Acute pancreatitis is an acute inflammation of the pancreas, varying in severity from mild abdominal pain to fulminant necrotizing pancreatitis and death.
A histopathologic specimen of fulminant necrotizing pancreatitis shows diffuse stippled necrosis of the pancreatic parenchyma and peripancreatic fat.
It has an incidence between 3.6 and 13.2 cases per 100,000 children. If episodes of acute inflammation completely resolve and then recur, it is termed acute recurrent pancreatitis.
It is thought that complete interval resolution of morphology and function occurs between episodes, unlike in cases of chronic pancreatitis.
The causes of acute pancreatitis include trauma, biliary tract stone disease, choledochal cyst, ductal developmental anomalies, drugs, metabolic derangements, and infections.
Most commonly, the cause is not apparent and is termed idiopathic. As the pancreas is fixed against the lumbar spine, trauma to the upper abdomen can fracture the pancreas or injure the major duct at that point.
Biliary stone disease, increasing in frequency in children, may lead to pancreatitis from transient pancreatic duct obstruction.
ERCP is safe and effective in children and is the preferred method for stone retrieval.
Drugs that are thought to induce pancreatitis include asparaginase and valproic acid.
Systemic illnesses and metabolic conditions, such as CF, Reye syndrome, Kawasaki disease, hyperlipidemias, and hypercalcemia, as well as viral infections and generalized bacterial sepsis, also can cause pancreatitis.
As discussed previously, the relative obstruction found in pancreas divisum also can cause recurring episodes of pancreatitis.
Symptomatic patients should undergo sphincteroplasty of the minor papilla.
Endoscopic stenting, with or without sphincterotomy, is the preferred treatment, with operation reserved for recurrent cases.
Choledochal cysts produce pancreatitis by pancreatic duct compression or bile reflux resulting from a long common biliary–pancreatic duct within the head of the pancreas.
Other rare ductal anomalies may result in obstruction and recurring bouts of pancreatitis.
Although acute pancreatitis has many etiologies, they all appear to share a common pathway of nonphysiologic calcium signaling in the pancreas, followed by the premature activation of acinar proenzymes.
These enzymes, especially trypsin, lead to acinar cell injury and cytokine release.
The cytokines, along with vascular dissemination of activated enzymes, free radical formation, and release of vasoactive substances, such as kallikreins and histamine, together mediate extrapancreatic inflammation.
How is acute pancreatitis diagnosed?
Diagnostic criteria for acute pancreatitis include at least two of the following: acute abdominal pain (especially in the epigastric region), serum amylase or lipase more than three times the upper limit of normal, and imaging findings characteristic or compatible with acute pancreatitis.
The abdomen is diffusely tender with signs of peritonitis, and distention occurs with a paucity of bowel sounds. In severe cases of necrotizing or hemorrhagic pancreatitis, hemorrhage may spread away from the pancreas along tissue planes, appearing as ecchymosis either in the flanks (Grey Turner sign) or at the umbilicus (Cullen sign). These ecchymoses generally take 1–2 days to develop.
Elevated amylase levels are helpful in the diagnosis, although a normal serum amylase level does not exclude pancreatitis.
Hyperamylasemia also may be caused by salivary inflammation/trauma, intestinal disease (such as perforation, ischemia, necrosis, or inflammation), and macroamylasemia.
Lipase has been suggested as an alternative marker, but can be falsely elevated in pancreatic cancer, macrolipasemia, renal insufficiency, cholecystitis, esophagitis, intestinal perforation, and hypertriglyceridemia.
Elevated lipase tends to be more sensitive in infants and toddlers and may also help differentiate pancreatitis from salivary trauma. The degree of enzyme elevation does not correlate with disease severity.
Imaging the abdomen is important as part of the evaluation of the patient with abdominal pain.
In the patient with pancreatitis, plain abdominal radiographs may reveal an isolated loop of intestine in the vicinity of the inflamed pancreas, termed the sentinel loop.
Pancreatic calcifications suggest chronic pancreatitis.
Plain chest radiographs should be performed in all patients with acute pancreatitis to look for evidence of pleural effusion and pulmonary edema.
Abdominal ultrasound (US) is useful in the evaluation of the patient with pancreatitis, but has limited applications. It is well established in the evaluation of biliary stone disease as the etiology for pancreatitis and can detect choledochal cysts and pancreatic pseudocysts as well.
Advanced techniques such as contrast-enhanced US and US elastography have also been shown to be useful in the diagnosis of pancreatitis and its complications, but their availability is limited to a few experienced centers.
Abdominal computed tomography (CT) provides much better resolution of the pancreas than US. Its primary role is in the detection of early and late complications, such as pancreatic necrosis, pseudocysts, and fluid collections, and should be reserved for patients with more severe pathology or recurrent symptomatology with an equivocal US. If necessary, CT can be combined with interventional procedures to drain fluid collections.
MRCP is a newer, noninvasive technique for evaluating the biliary tree and pancreatic duct. It is the initial imaging study of choice for the evaluation of pancreatic ductal anatomy in children with recurrent or unexplained pancreatitis.
Studies comparing MRCP and ERCP show high concordance in diagnoses. Its disadvantages are that it does not allow for therapeutic intervention (though it may direct the type of intervention necessary), its poor spatial resolution limits the visualization of ducts in smaller children, and it usually requires anesthesia in the pediatric age group.
The most frequent indication for ERCP in children is in the diagnosis or treatment of acute, recurrent, or chronic pancreatitis.
A large single-institution retrospective study found a low rate of post-ERCP complications and a high therapeutic success rate. In that study, ERCP was shown to be particularly useful in the diagnosis of recurrent pancreatitis, though in only 60% of patients was an organic etiology found. Sphincter of Oddi manometry was particularly useful in establishing a diagnosis when no anatomic abnormalities were present.
How is acute pancreatitis managed?
The treatment for pancreatitis has remained unchanged for decades. The mainstays of therapy are pain control, intravenous fluid resuscitation, pancreatic rest, and monitoring for complications.
1) Fluid resuscitation
Fluid resuscitation and maintenance should be guided toward a goal urine output of 2 mL/kg/h measured by an indwelling urinary catheter.
Because of circulating cytokines, activated digestive enzymes, and other proinflammatory molecules, extracellular fluid losses can be enormous.
Constant monitoring is necessary to avoid the development of severe hypovolemia.
2) Pancreatic rest
Patients with severe acute pancreatitis may require nasogastric decompression.
Most patients receive histamine-2 (H2 ) receptor antagonists to reduce exposure of the duodenal secretin-producing cells to gastric acid, a potent stimulator of pancreatic secretion.
This therapeutic regimen is logical but empiric, because no studies have shown improvement in outcomes with these interventions.
The effectiveness of somatostatin in the treatment of pancreatitis is equivocal and probably serves more to mitigate complications of pancreatitis rather than to treat the disease itself. Further studies are needed to clearly define its role in both adults and children.
3) Nutrition
Nutrition is critically important in patients with pancreatitis. The past decade has seen a paradigm shift in the nutritional management of patients with pancreatitis.
Early nutrition, within the first 72 hours, is still recommended.
However, enteral nutrition (EN) has become the preferred method over total parenteral nutrition (TPN).
Mild to moderate cases of acute pancreatitis often resolve prior to requiring EN or TPN.
More severe cases should be treated with EN via a nasojejunal tube, though studies have demonstrated tolerance of nasogastric feeding in severe pancreatitis as well.
TPN use, especially early in the disease course during the peak inflammatory response, has been associated with increased length of stay and delayed advancement of diet.
When EN is contraindicated, some advocate waiting as long as 5 days prior to starting TPN.
Compared with TPN, EN has been shown to decrease length of stay, reduce the need for surgery, and reduce the risk of infection.
When restarting a diet, conservatively determined by resolution of symptoms, there appears to be no difference between clear liquids and solid food as the initial meal.
Unfortunately, these data come almost exclusively from the adult population as pediatric trials are lacking.
4) Pain control
Adequate analgesia is critical to minimizing the physiologic stress that develops from pain.
Although meperidine (Demerol) was once advocated because morphine was thought to cause spasm of the Sphincter of Oddi, no clinical trials have shown superiority of meperidine over other narcotic analgesics.
Large doses of meperidine, however, are associated with the risk of seizure, euphoria, and drug interactions, suggesting other narcotics such as morphine and fentanyl may be safer alternatives.
The diagnosis of pancreatitis must be certain prior to initiating treatment with high doses of narcotics as these may mask signs of serious nonpancreatic pathology, such as intestinal or gastric perforations.
5) Monitoring and indications for operation
As pancreatitis progresses in severity, patients need to be monitored closely for signs of multisystem organ failure.
Pleural effusions, pulmonary edema, and tense abdominal distention may lead to hypoxia requiring intubation and acute respiratory distress syndrome.
Hypocalcemia, hypomagnesemia, anemia from hemorrhage, hyperglycemia, renal failure, and late sepsis also can be seen in these patients.
Disagreement exists regarding the use of prophylactic antibiotics in severe cases of pancreatitis.
The most recent adult data suggest a trend toward decreased mortality and infection with prophylactic antibiotics, but this study failed to reach statistical significance.
Imipenem is the antibiotic therapy of choice when necessary.
Operative exploration is usually not necessary in acute pancreatitis. However, exploration is needed in patients with infected necrotic pancreatitis or a pancreatic abscess.
Infected pancreatic necrosis increases mortality significantly. Diagnosis is typically by CT pancreatography, with confirmation of infection by fine-needle aspiration, clinical deterioration, or positive cultures.
The latest adult data suggest that infected necrosis or peripancreatic abscesses are best treated in a stepwise manner from least to most invasive.
When feasible, percutaneous drainage should be followed by minimally invasive necrosectomy if the patient fails to improve. Delayed operative therapy has been shown to improve mortality when compared with the rate in primary necrosectomy.
What are pancreatic pseudocysts and how are they managed?
Pancreatic pseudocyst is a complication of trauma or pancreatitis that forms after injury to the pancreatic ductal system.
The extravasated pancreatic enzymes and digested tissue are contained by the formation of a cavity composed from a fibroblastic reaction and inflammation that lacks an epithelial lining.
The acute pseudocyst has an irregular wall on CT scan, is tender, and usually develops shortly after an episode of acute pancreatitis or trauma.
Chronic pseudocysts are usually spherical with a thick wall and are commonly seen in patients with chronic pancreatitis.
The distinction is important because half of acute pseudocysts resolve without treatment, while chronic pseudocysts rarely spontaneously resolve.
An acute pseudocyst matures and forms a thick fibrous wall in 4–6 weeks, allowing for drainage.
Those smaller than 5 cm in diameter usually spontaneously regress.
When compared with those in adults, pseudocysts in children tend to resolve more frequently with medical therapy alone. There are anecdotal reports of pseudocyst resolution in children after treatment with long-acting somatostatin analogs.
Pancreatic pseudocysts that persist or are symptomatic require either a drainage procedure or excision.
Endoscopic treatment, well established in adults, has been reported to be safe and efficacious in children as well. This should be performed only at centers with sufficient experience with these techniques.
Other options include laparoscopic transgastric and intragastric drainage into the stomach or jejunum.
Percutaneous drainage is the preferred approach for an infected pseudocyst because these cysts typically have thin, weak walls that are not amenable to internal drainage.
The three major complications of pancreatic pseudocysts are hemorrhage, rupture, and infection.
Hemorrhage is the most serious complication and usually results from pressure and erosion of the cyst into a nearby visceral vessel. These patients require emergency angiography with embolization.
Rupture or infection of a pseudocyst is uncommon. In both cases, external drainage is indicated.
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Pancreatic tumors in children are quite rare. The most commonly encountered lesion of the pancreas in pediatric surgical practice is a pancreatic fluid collection or pseudocyst following pancreatic trauma or an episode of pancreatitis. In fact, one of the challenges of a pediatric surgeon is to decide when a lesion is not likely to be a pseudocyst. History is extremely critical in arriving at the correct diagnosis of a pancreatic cystic lesion.
Fluid collections and pseudocysts are more likely to occur following an episode of severe pancreatitis in children than in adults.
However, they also tend to behave in a less-aggressive manner in the pediatric age group.
A pseudocyst is defined as a pancreatic fluid collection that has been present for 4 weeks or more.
As mentioned in the index case, multiple treatment modalities now exist for the treatment of these lesions.
In the past, internal drainage to the stomach or a small intestinal loop was the most commonly practiced treatment.
Typically, pseudocysts had to reach a size of 6 cm and have a wall at least 6-mm thick to be amenable to internal drainage.
However, the treatment paradigm has changed to one based upon symptoms.
Asymptomatic pseudocysts of any size, etiology, and location within the pancreas may be observed.
The fear of pseudocyst rupture or hemorrhage is unfounded.
The surgical dictum of “putting the pancreas to rest” is no longer applicable and enteral feedings by any route have been found to be associated with better outcomes.
Sherif
How is ascites following pancreatic trauma or surgery managed?
Ascites in children can follow pancreatic trauma or pancreatic surgery.
Free fluid results from the uncontained leakage from a major pancreatic ductal injury.
When suspected, CT, ERCP, or MRCP should be performed to assess for a ductal injury.
Nonoperative management initially consists of bowel rest with hyperalimentation and the use of long-acting somatostatin analogs.
In many cases, the ascites resolves spontaneously with this treatment.
The recent literature is full of controversy regarding optimal management for pancreatic trauma with a ductal injury.
More complications, a longer time to goal feeds, and a higher rate of pseudocyst formation were found with nonoperative management in two recent retrospective reviews.
On the other hand, other recent studies support nonoperative management of pancreatic trauma in children even in the presence of a ductal injury.
When operative treatment is needed, depending on the nature and site of the injury, drainage alone may be sufficient.
Distal ductal injuries can be treated with distal pancreatic resection, and recent experience has shown that the laparoscopic approach is safe and feasible.
Proximal injuries require a Roux-en-Y jejunal onlay anastomosis to preserve pancreatic tissue.
Pseudocyst formation is common in this patient population.
How are pancreatic fistulas managed?
A pancreatic fistula can develop postoperatively or from nonoperative management.
Most low-output fistulas close spontaneously but can drain for several months.
Long-acting somatostatin analogs decrease fistula output and accelerate the rate of closure, but do not appear to induce closure of fistulas that would not otherwise have closed.
Managing a pancreatic fistula centers around maintaining nutrition, with hyperalimentation necessary if enteral feeding increases fistula output, and ensuring the fistula tract does not become obstructed.
Operative intervention with a Roux-en-Y jejunostomy anastomosed to the fistula site is usually curative if the fistula fails conservative management.
How does chronic pancreatitis differ from acute pancreatitis?
Chronic pancreatitis is distinguished from acute pancreatitis by the irreversibility of the changes associated with the inflammation.
Chronic pancreatitis remains a substantial clinical problem, afflicting roughly 140,000 individuals in the United States alone.
The disease entails several clinical problems:
(1) severe and intractable pain typically requiring narcotics;
(2) malabsorption due to loss of pancreatic digestive enzymes from the exocrine pancreas, requiring chronic enzyme replacement for life;
(3) life-threatening complications such as pancreatic pseudocyst, pancreatic ascites, biliary obstruction, etc.;
(4) a 13-fold increased risk of pancreatic cancer48 ; and
(5) the development of insulinopenia and overt diabetes mellitus in over half of patients (and probably most patients if they live long enough).
Diabetes is likely due to the proximity of the endocrine pancreas to the inflamed exocrine pancreas.
How is chronic pancreatitis classified?
Chronic pancreatitis can be classified as either calcifying or noncalcifying.
The calcifying form, most common in hereditary or idiopathic pancreatitis, is more prevalent than the obstructive form in children and is associated with intraductal pancreatic stones, pseudocysts, and more aggressive scar formation.
The obstructive type of chronic pancreatitis, which is associated with an anatomic or functional obstruction, is generally less severe with less scarring than calcifying pancreatitis.
Single institutional experiences vary as to distributions in etiology, though the predominant causes are hereditary/genetic, obstructive, or idiopathic.
When is genetic testing indicated for chronic pancreatitis?
The discovery of a genetic basis for certain forms of chronic pancreatitis represents a major breakthrough in our understanding of its pathogenesis.
Current thinking is that familial pancreatitis results from a combination of environmental triggers, genetic susceptibility, and an inappropriate immune response leading to chronic inflammation and fibrosis.
Hereditary pancreatitis, the most common genetic cause of pancreatitis, can result from abnormalities in the cationic trypsinogen gene PRSS1.
This autosomal dominant condition most commonly results from one of two mutations that either prevent degradation of prematurely activated trypsin or make trypsin resistant to inactivation.
Penetrance in this condition is approximately 80%. Other gene mutations implicated in chronic pancreatitis are SPINK1 and CFTR.
Genetic testing is recommended for children with recurrent, idiopathic pancreatitis, with or without a family history of pancreatitis.
Notably, patients with hereditary pancreatitis have a markedly increased risk of pancreatic cancer after age 50 years.
What are causes of obstructive pancreatitis?
Obstructive pancreatitis is most often due to an anatomic or functional obstruction of the pancreatic duct.
The most common anatomic causes are pancreas divisum followed by choledochal cysts.
Uncertainty exists as to why a minority of patients with pancreas divisum develop chronic pancreatitis while most do not.
The literature suggests that potential causes are the anatomic variant, structural narrowing of the minor papilla, sphincter of Oddi dysfunction, or the relatively high association with CFTR mutations.
Many patients with ductal dilatation and anatomic or functional obstruction clearly improve with endoscopic sphincterotomy and/or stents.
Pancreatic dyskinesia, though not well studied in children, may be improved by endoscopic sphincterotomy and sometimes temporary stent placement.
For those in whom endoscopic treatment is not feasible or fails, individualized surgical treatment is reasonable based on the patient’s ductal anatomy, level of obstruction, and severity of pancreatic fibrosis.
How is chronic pancreatitis diagnosed?
Chronic pancreatitis can manifest with a characteristic pain, diminished pancreatic function, and radiographic abnormalities.
Increased stool fat, diabetes, and steatorrhea are signs of pancreatic insufficiency.
Frequently on a CT scan, the pancreas has microcalcifications throughout the parenchyma and calcified stones in the duct.
Additionally, pancreatic pseudocysts or inflammation may be seen on the CT scan.
ERCP and MRCP can evaluate the ductal anatomy and identify anatomic causes of chronic pancreatitis.
Only ERCP provides a means for evaluating sphincter pressure measurements for functional obstruction.
How is chronic pancreatitis treated?
Therapy for chronic pancreatitis is directed toward palliation of symptoms.
Initial management for acute exacerbations is pain control and hydration.
Steatorrhea indicates the need for pancreatic enzyme replacement.
In general, these patients respond better with small, frequent meals.
The diabetes that results from chronic pancreatitis tends to be unusually brittle, with a propensity for severe hypoglycemic episodes after even low doses of insulin.
This hypersensitivity to insulin may be due to the loss of entire islets, which includes the glucagon producing alpha cells that normally oppose the glucoselowering effect of insulin.
In patients with chronic pancreatitis who have severe, intractable pain, ERCP or MRCP may help locate correctable problems such as large stones or a stricture with distal duct dilatation.
Surgical options in chronic pancreatitis include sphincteroplasty, excision of localized pancreatitis, subtotal pancreatectomy, lateral pancreaticojejunostomy (modified Puestow procedure), and the duodenum or pylorus-preserving Whipple.
Individualization of the operative approach and maximization of pancreatic ductal drainage are key.
Patients failing more conservative surgical management may require a more definitive procedure to achieve symptomatic relief.
Although the operative results in patients with hereditary pancreatitis are generally disappointing, evidence exists that complicated patients treated with a modified Puestow procedure may experience an improved quality of life (QOL), with subsequent improvement in pancreatic function and nutritional status.
Unlike adults with hereditary pancreatitis, some reversal of the steatorrhea may be seen in children.
What are the causes of persistent hypoglycemia in the pediatric population?
In newborns and young infants, the major causes are:
(1) congenital hyperinsulinism of infancy, previously called nesidioblastosis;
(2) a lack of substrate for gluconeogenesis (e.g., glycogen storage disease); and
(3) inadequate gluconeogenic hormones (e.g., hypothyroidism or growth hormone deficiency).
In children with the onset of hypoglycemia after 1 year of age, the causes are different, with insulinoma being the most common.
What is congenital hyperinsulinism?
Nesidioblastosis, the original term for what is now called congenital hyperinsulinism of infancy (CHI), comes from the Greek nesidio, meaning “island,” and blast, meaning “new formation.”
Nesidioblasts were originally thought to be progenitor cells in the wall of the pancreatic ducts, which overproliferate in patients with this condition. With the advent of genetic analysis, this pathogenesis is now known to be incorrect.
Mutations in seven genes are currently known to cause CHI, though roughly half of cases are caused by genetic malformations not yet understood.
Initially discovered was the loss-of-function mutations in the SUR1 and Kir6.2 components of the ATP-sensitive potassium channel (KATP) found in the cell membrane of the pancreatic β-cell.
These mutations either impair the ability of Mg-adenosine diphosphate (ADP) to stimulate channel activity or affect the expression of the KATP channels at the surface membrane, resulting in continuous depolarization of the β-cell membrane and dysregulated insulin secretion.
Heterozygous gain-of-function mutations in GULD1, the mitochondrial gene encoding glutamate dehydrogenase, leads to CHI caused by the insensitivity of the enzyme to inhibition by guanosine-5′-triphosphate.
This gain-of-function mutation results in a milder form of CHI, which may be diagnosed later in childhood, and is associated with hyperammonemia and occasionally epilepsy.
Heterozygous loss-of-function mutations in HNF4A, an islet transcription factor gene, are also associated with CHI through unknown mechanisms.
More rare are cases of CHI caused by mutations in glucokinase (GCK), hydroxyacyl-coenzyme A dehydrogenase (HADH), and the solute carrier SLC16A1.
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The earliest indication for pancreatic resection due to symptomatic lesions occurs in hypoglycemic neonates.
Formerly called nesidioblastosis, the condition is now referred to as congenital hyperinsulinism or persistent hyperinsulinemic hypoglycemia of infancy.
Significant advances have occurred in the diagnosis and treatment of these lesions over the last two decades, leading to important changes in the treatment paradigm.
It is now recognized that the disease consists of two forms, a diffuse and a focal form. Differentiation between the two is essential prior to surgical treatment and relies on genetic testing and 18 fluorodihydroxyphenylalanine positron emission tomography/computed tomography scan (18 F-DOPA PET/CT).
At least half the patients have focal disease and are cured by segmental pancreatectomy.
The diffuse form of the disease represents a spectrum of severity based on the amount of glucose infusion necessary to maintain euglycemia.
Medical management with diazoxide, octreotide, and other agents may be able to control less severe cases.
Patients who do not respond to maximal medical management require a 95% pancreatectomy, leaving a small pancreatic rim along the duodenum.
The outcomes of these patients are inferior to those with focal disease.
Congenital hyperinsulinism is exceedingly rare and several centers around the world have developed enhanced medical and surgical expertise in both its diagnosis and treatment.
Strong consideration should be given to referral of these patients to one of these centers if local expertise is unavailable.
Sherif
What are the two types of congenital hyperinsulism?
CHI occurs in a focal and diffuse type, the differentiation of which is critical for operative management.
Unfortunately, however, the clinical presentation is identical.
Patients with SUR1 mutations often have the focal type. The focal type is actually a focal adenomatous hyperplasia, different from an adenoma.
Histologically, it is seen as a confluence of hyperplastic but otherwise normalappearing islets.
There is little insulin present within the lesion due to excess secretion, while uninvolved islets outside are small with high insulin content.
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The diffuse type is macroscopically normal, but careful evaluation of the islets reveals enlarged β-cells with abnormally large nuclei, a large Golgi apparatus, and weak insulin staining due to hypersecretion.
What is the clinical presentation of congenital hyperinsulinism?
CHI patients typically develop hypoglycemia shortly after birth, though it may manifest at a later age.
Infants with CHI are often macrosomic.
Symptoms may be subtle, such as lethargy and irritability, or severe with apnea, seizures, and coma.
Simultaneous insulin and glucose measurements show a high ratio of insulin to glucose, keeping in mind that insulin levels may be normal but inappropriate in the presence of hypoglycemia.
These patients differ from insulinoma patients, who usually have high absolute insulin levels.
Another powerful indicator of CHI is a glucose requirement greater than 8 mg/kg/min.
Owing to the much higher incidence of insulinoma, patients older than 1 year at the onset of hypoglycemia should be evaluated for both conditions.
How is congenital hyperinsulinism treated?
Stabilization of the CHI patient includes frequent intermittent or continuous feeding, with the addition of intravenous glucose as needed.
Central venous access is advised because adequate venous access is lifesaving and high concentrations of intravenous glucose may be necessary.
Maintaining normoglycemia is key to preventing potentially disabling hypoglycemic brain injury.
Intramuscular glucagon can be used as a temporizing measure until definitive venous access is obtained.
Treatment of CHI begins with medical management. Diazoxide remains a mainstay of therapy.
Diazoxide binds the SUR1 component of the KATP channel and maintains it in a persistently open state, preventing insulin secretion.
Patients with diazoxide-sensitive CHI who can tolerate fasting can be managed medically until they outgrow their condition.
Those unresponsive to diazoxide should be managed with frequent feedings, glucose infusions, and somatostatin analogs.
Somatostatin analogs inhibit pancreatic insulin secretion and can be administered subcutaneously either intermittently or continuously by a pump.
Somatostatin analogs are associated with gallstones and biliary sludge, and have been implicated in cases of necrotizing enterocolitis.
Medical failure to control hypoglycemia necessitates surgical intervention.
Distinguishing diffuse versus focal CHI is critical for operative planning.
The development of a fluoro-18-Ldihydroxyphenylalanine (18 F-DOPA) positron emission tomography–CT (PET-CT) scanner has replaced pancreatic venous sampling as the optimal method for delineating focal versus diffuse disease with a sensitivity of 94% and specificity of 100%.
Intraoperative US can provide additional anatomic detail to help avoid injury to the biliary tree.
For the focal type, resection of the hypermetabolic focus is curative. Focal lesions in the head may require duodenum-preserving pancreatic head resection and distal pancreaticojejunostomy with excision of distal lesions via spleen-preserving distal pancreatectomy.
In patients with diffuse disease, a near-total pancreatectomy is needed, leaving only a rim of pancreatic tissue along the common bile duct.
The laparoscopic approach for both procedures has been reported, but data are limited.
Operative complications include bile duct injury, pancreatic insufficiency, and the need for repeat pancreatic resection due to persistent hypoglycemia.
Alternative forms of hyperinsulinemic hypoglycemia can arise secondary to maternal diabetes, birth asphyxia, or intrauterine growth restriction (IUGR).
In these patients, the condition is transient, resolving for most patients within several days.
A subgroup of patients with IUGR and prenatal asphyxia will have a prolonged condition that requires diazoxide for several months prior to resolution.
Approximately 50% of children with Beckwith–Wiedemann syndrome have a CHI-like condition that tends to resolve spontaneously, but 5% will eventually require pancreatectomy.
What is the prognosis for congenital hyperinsulinism?
The long-term outlook for these patients depends primarily on the age at onset, which reflects severity of disease, and on an expeditious diagnosis because a late diagnosis results in a higher incidence of neurologic sequelae.
Most patients seem to grow out of the disease after several years, implying diminished activity of the β-cells.
Near-total pancreatectomy in one series was associated with a 91% incidence of insulin-dependent diabetes by age 14; however, no patient with focal resection required long-term insulin therapy, emphasizing the need for a conservative operative approach when possible.
What is glycogen storage disease?
Glycogen storage disease type Ia (GSD Ia) and Ib classically appear as severe hypoglycemia in infants caused by the inability to dephosphorylate hepatic glycogen subunits into glucose.
GSD Ia is caused by inactivating mutations of the glucose-6-phosphatase enzyme itself, whereas GSD Ib results from inactivating mutations of the glucose6-phosphate transporter.
Hypoglycemia becomes apparent when the time between feedings increases and the liver fails to generate glucose from glycogen stores.
It is clinically diagnosed by hypoglycemia, hypoinsulinemia, hepatomegaly, nephromegaly, ketosis, and hyperlipidemia.
Central venous access is required for continuous infusion of highly concentrated glucose.
Survivors into adulthood have an increased incidence of hepatic adenoma after age 25 and have a 10% risk of malignant transformation.
Liver transplantation ultimately becomes necessary in these patients.
What are the pancreatic endocrine tumors seen in infants and children?
The only pancreatic endocrine tumors seen in infants and children are insulinomas, gastrinomas, and VIPomas.
VIPoma is a tumor of vasoactive intestinal peptide (VIP) producing cells and only case reports exist in children.
Insulinoma is the most common of the three, though still quite rare among pediatric tumors in general.
Only 10% of insulinomas are malignant, and these tend to spread to the liver and peripancreatic lymph nodes.
Insulinomas cause symptoms of hypoglycemia, including dizziness, headaches, confusion, sweating, and seizures.
The classic Whipple triad was described in patients with insulinoma and consists of symptoms of hypoglycemia with fasting, glucose levels less than half of normal when fasting, and relief of symptoms with glucose administration.
Patients are typically in their adolescence, though younger children have been described with insulinoma.
The lesions are usually solitary, except in multiple endocrine neoplasia type I (MEN I), in which multiple insulinomas may be found.
What is the gold standard for diagnosing insulinoma in pediatric patients?
The gold standard test for insulinoma is the 72-hour fast, though studies have shown that a positive result is achieved in 80–90% of patients with insulinoma after a shorter 24or 48-hour fast, respectively.
While fasting, periodic blood glucose levels are obtained.
When the patient’s blood glucose falls below 50 mg/dL and symptoms are present, blood is drawn for plasma glucose, C-peptide, proinsulin, insulin, β-hydroxybutyrate, and sulfonylureas.
Administration of exogenous insulin, followed by measurement of the Cpeptide level, can be suggestive of an insulinoma, but is not completely reliable.
Measuring the insulin-to-glucose ratio is no longer needed.
Preoperative localization is challenging but can be extremely helpful.
Extrapancreatic insulinomas are rare. Most experts advocate for both transabdominal US and CT for initial localization, which identifies more than half of the tumors.
Centers experienced with endoscopic US also have reported good success in detecting insulinomas, but this expertise is not widely available.
Magnetic resonance imaging (MRI) is most useful for detecting liver metastases.
If noninvasive studies fail to identify the tumor, intra-arterial calcium stimulation via a catheter in several visceral arteries with parallel venous sampling from the right hepatic vein has been reported to regionally localize insulinomas in 80–94% of cases.
Intraoperative US is strongly advocated for identification of adjacent biliary and vascular structures, and as a method of last resort if nonoperative localization fails.
What is the management for pediatric insulinoma?
All patients with insulinoma should undergo resection.
Insulinomas are pink, firm, encapsulated, and usually amenable to enucleation.
In most cases, through preoperative and intraoperative analysis, the tumors can be localized, but in patients in whom they cannot be localized, blind distal pancreatic resection is no longer advised.
The distinction between benign and malignant lesions is difficult and is based on tumor size (<2 cm tend to be benign) and the presence of metastases.
Insulinomas that are hard, cause puckering of surrounding tissues, appear infiltrating, or cause distal pancreatic duct dilation should be assumed malignant and resected with a margin instead of enucleated.
Malignant tumors can be treated with chemotherapy, biotherapy (such as octreotide), hepatic artery embolization/chemoembolization, radiation therapy, or radiofrequency ablation.
How is pancreatic gastrinoma diagnosed?
Fetal gastrin-producing cells in the pancreas are believed to give rise to pancreatic gastrinoma.
In the fetus, the primary source of gastrin is the pancreas. After birth, the gastric antrum becomes the principal source.
Zollinger-Ellison syndrome (ZES) consists of gastric hypersecretion with severe peptic ulcer disease and a gastrin-producing tumor, classically in the pancreas.
ZES may occur as part of the MEN I syndrome or sporadically.
Gastrinomas are now understood to be frequently malignant, especially with spread to the liver, and their removal is strongly advocated.
The diagnosis of a gastrinoma is based on hypergastrinemia and gastric hypersecretion.
Fasting gastrin levels are usually elevated but can be normal.
Patients suspected of having ZES should undergo a secretin stimulation test, which is considered positive if the gastrin level increases by 200 pg/mL or more.
Localization can be challenging because the tumors are often small and may be extrapancreatic, but CT, MRI, endoscopic US, and indium-111 octreotide scintigraphy have been utilized to localize the tumors.
Extrapancreatic tumors are often found in the duodenal wall.
How is pancreatic gastrinoma managed?
Medically, patients should initially be treated with omeprazole to control peptic ulcer disease and prevent bleeding.
All disease should be excised if possible to control symptoms and help prevent metastases.
Patients cured by resection should be followed closely as recurrence is common.
Medical treatment for unresectable disease includes proton pump inhibitors and octreotide.
Tumor debulking in unresectable cases is recommended to improve patient QOL and increase life expectancy.
Chemotherapy has been utilized in a few cases with good results.
There is a report of a patient with multiple gastrinomas managed medically who survived 26 years before succumbing to unrelated causes.
How are exocrine pancreatic cancers managed in pediatric patients?
Exocrine pancreatic cancers account for roughly half of pancreatic neoplasms in children.
Whereas ductal adenocarcinoma is most common in adults, its embryonic counterpart pancreatoblastoma is more common in children.
Pancreatoblastoma is believed to result from the persistence of embryonic pancreatic progenitor cells beyond the eighth week of gestation. It tends to be diagnosed in early childhood and is more common in boys and those of Asian descent. An allelic loss on 11p is often associated and suggests a similar pathogenesis with Beckwith–Wiedemann syndrome and other embryonic tumors.
A large multicenter review demonstrated that the tumor distribution was homogenous throughout the pancreas, most were larger than 5 cm at presentation, and over half had distant metastases.
Elevation of serum α-fetoprotein was an inconsistent feature.
The prognosis is relatively good with complete resection and with appropriate neoadjuvant and/or adjuvant chemotherapy and radiation therapy. Relapse is common, so continued monitoring is essential.
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Acinar cell carcinoma and ductal adenocarcinoma are less common pancreatic exocrine tumors.
Ductal adenocarcinoma is infrequently reported in the pediatric literature, and no definitive recommendations are possible.
Acinar cell carcinoma is comparatively more common.
Complete resection for both tumor types appears necessary with appropriate provision of neoadjuvant or adjuvant chemotherapy based on pretreatment staging.
Long-term survival improves with an earlier stage at presentation.
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Occurring slightly less frequently than pancreatoblastoma is the solid pseudopapillary tumor, also known as a papillary-cystic tumor or Frantz tumor.
It has a female preponderance and is derived from exocrine cells but without acinar or ductal structures.
Presenting symptoms often include a palpable abdominal mass and abdominal pain.
These tumors can be very large at the time of diagnosis.
They are very slow growing, and there are reports of patients surviving 20 years after diagnosis without treatment.
Although these tumors are rarely metastatic, excision of regional and distal metastases greatly improves survival.
Even with its indolent nature, an aggressive approach with complete resection is recommended as one retrospective study of patients with incomplete resections showed poor long-term survival.
How is chronic relapsing pancreatitis diagnosed in children?
The degree of permanent damage to the pancreas may be assessed by blood tests (pancreatic enzymes), stool tests (pancreatic enzymes, fecal fat), and noninvasive tests of pancreatic function such as the pancreatic stimulation (secretin) test.
In 30% to 50% of adolescents and adults with chronic pancreatitis, plain radiographs of the abdomen reveal pancreatic calcification. Calcification is diagnostic of chronic pancreatitis, even if clinical evidence of pancreatic disease is absent. However, the incidence of calcification in children with chronic relapsing pancreatitis is low, except in younger children with hereditary pancreatitis, in whom the incidence is high.
US is ideal for examining the pancreas in children. Dilatation of the pancreatic or biliary tracts may be noted, and calcification and complications such as pseudocysts, abscesses, calculi, and ascites can be seen.
CT is useful for visualizing the size of the pancreas and its ducts and for detecting small calculi that may be missed on plain radiographs and US.
ERCP is an important tool in the diagnosis and management of chronic relapsing pancreatitis in adults and children. Pancreaticobiliary malunion with or without dilatation of the bile duct may be detected.
ERCP is up to 90% accurate in diagnosing ductal abnormalities. However, as described earlier, MRCP has been greatly refined in the past decade. MRCP is considered to be equivalent to ERCP for the diagnosis of many pancreatic and biliary conditions and is preferable because it is noninvasive and safer.
Coran
What is the management for pancreas divisum?
The embryology of this entity was described in the first section of this chapter. Pancreas divisum is suspected on MRCP or ERCP when the duct of Wirsung fails to be visualized after injection of the major papilla or when it is attenuated and rudimentary.
MRCP is a useful and noninvasive diagnostic tool for pancreas divisum, but ERCP can provide detailed information on the pancreatic duct.
If pancreas divisum is suspected after injection of the papilla of Vater, an attempt should be made to find and cannulate the minor papilla, but this is possible in less than half the cases because of its small size and the angle at which it meets the duodenum.
If the minor papilla can be entered, ERCP will demonstrate that the duct of Santorini is the dominant duct and that it extends the entire length of the body and tail of the pancreas.
Imaging of the duct of Santorini occasionally demonstrates dilatation, irregularity, or stricture suggestive of chronic pancreatitis.
Autopsy studies have suggested that pancreas divisum, which is found in 4% to 11% of patients, is the most common congenital anomaly of the pancreas.
When absence of the duct of Wirsung is associated with pancreas divisum, approximately 10% of affected patients have anomalous anatomy resulting in most or all of the pancreatic secretions draining by means of the accessory papilla.
Pancreas divisum should not be regarded as a disease. However, if the orifice of the accessory papilla is stenotic, pancreatitis can result. Stenosis of the minor papilla is probably developmental because the orifice is usually small with no evidence of inflammation.
The incidence of pancreas divisum may be significantly higher in patients with unexplained recurrent pancreatitis, and it was detected in up to 25% of patients. Neblett and O’Neill reported that pancreas divisum was identified in 7.4% of all children with pancreatitis and 19.2% of children with relapsing or chronic pancreatitis. In 10 patients with pancreas divisum, 8 had complete pancreas divisum and 2 had incomplete variants.
The primary goal of treatment of pancreas divisum associated with pancreatitis is to establish adequate drainage of the duct of Santorini.
The progression of disease to pancreatic insufficiency can be arrested when the obstruction is relieved early.
Correction may not only preserve pancreatic function but may also help ensure that normal growth and development occur.
Several reports have shown that adequate drainage of the duct of Santorini can be achieved with accessory papilla sphincteroplasty. A report by Adzick and colleagues delineated the technical details of the operative procedure.
Endoscopic sphincterotomy has been performed, but restenosis and recurrence of symptoms have been reported.
If chronic pancreatitis has developed in the presence of a dilated duct, longitudinal pancreaticojejunostomy should be considered.
Neblett and O’Neill 61 reported that 8 of 10 patients with pancreas divisum underwent surgery: 7 underwent transduodenal sphincteroplasty of the accessory papilla, along with sphincteroplasty of the major papilla in 2 (plus septoplasty in 1). Three patients underwent longitudinal pancreaticojejunostomy, as a primary procedure in one patient with mid-ductal stenosis and in two because of recurring pancreatitis after sphincteroplasty without endocrine and exocrine pancreatic insufficiency.
Surgical intervention is directed toward relief of ductal obstruction and may involve accessory duct sphincteroplasty alone or in conjunction with major sphincteroplasty and septoplasty.
Patients with more distal ductal obstruction or ductal ectasia may benefit from pancreaticojejunostomy.
In an extremely rare case, Miyano and colleagues treated a patient with coexistence of pancreas divisum, choledochal cyst, and pancreaticobiliary malunion. This patient underwent complete excision of the choledochal cyst with a Roux-en-Y hepaticojejunostomy, followed by transduodenal papilloplasty to allow complete drainage of the common channel.
Coran
How are pancreatic pseudocysts diagnosed in children?
Pancreatic pseudocysts are localized collections of pancreatic secretions that do not have an epithelial lining and develop after pancreatic injury, inflammation, or duct obstruction.
The most common causes of pseudocysts in children are trauma and infection.
Drug-induced acute pancreatitis such as with valproic acid is also a rare cause of pancreatic pseudocyst.
These cysts typically lie in the lesser sac behind the stomach and are composed of a fibrous capsule surrounded by inflamed connective tissue. The capsule of the cyst may also be formed by neighboring tissue such as the stomach, duodenum, colon, small intestine, or omentum.
Pseudocyst fluid is clear or straw colored in most cases and may contain toothpaste-like debris.
The amylase level of cyst fluid is typically higher than 50,000 Somogyi U/mL.
Diagnosis
The presence of a pancreatic pseudocyst is suggested by a history of blunt abdominal trauma; an illness resembling pancreatitis, possibly followed by a symptom-free interval of weeks to months; or palpation of a mass in the epigastrium or left upper quadrant.
Abdominal pain is the most common symptom, with jaundice, chest pain, signs of gastric obstruction, vomiting, gastrointestinal hemorrhage, weight loss, fever, and ascites also being features.
US, CT, and magnetic resonance imaging (MRI) are helpful and accurate in diagnosis. These studies are also invaluable for evaluating the thickness of the cyst wall and for observing changes in the cyst during the ensuing period of treatment.
ERCP is often useful because it can definitively determine the status of the pancreatic duct and thus guide surgical interventions.
Rarely, pancreatic pseudocysts can extend into the mediastinum in children.
Coran
How are pancreatic pseudocysts treated?
Optimal management of a pancreatic pseudocyst remains controversial. Treatment options range from conservative medical management to surgical drainage.
Conventional management involves supportive therapy over a 6-week waiting period, during which time either the cyst resolves spontaneously or the cyst wall undergoes fibrous maturation, thereby permitting internal surgical drainage to the stomach or jejunum.
This 6-week interval is what has traditionally been accepted, but CT may demonstrate thickening of the cyst wall sufficient to hold sutures as early as 3 to 4 weeks.
Surgical drainage is usually performed in adults when necessary but is controversial in children because some pancreatic pseudocysts in this group resolve without surgical intervention and have a low risk for recurrence.
Pseudocysts from nontraumatic etiologies are more likely to require surgical intervention, whereas traumatic pseudocysts are more amenable to nonoperative treatment.
Octreotide acetate, a long-acting analogue of somatostatin, may facilitate medical management of pancreatic pseudocysts.
A significant risk for complications such as infection or major hemorrhage in untreated pseudocysts or persistence of severe symptoms may be an indication for earlier intervention.
If the patient cannot withstand major surgery, external drainage is preferred.
There is significant evidence indicating that internal drainage, especially transgastric cystogastrostomy or Roux-en-Y cystojejunostomy, is effective in the treatment of pancreatic pseudocyst.
Roux-en-Y cystojejunostomy is the most widely used internal drainage procedure for this problem and is associated with the lowest rate of complications and recurrence.
In contrast to this approach, others have reported that percutaneous drainage and endoscopic transmural drainage are safe and efficient procedures. However, it is generally recognized that external drainage carries a higher risk for complications such as fistula formation and a higher recurrence rate than internal drainage does.
Internal drainage procedures cannot be accomplished until the wall of the pseudocyst has matured. Recent studies have shown that internal drainage should be performed in patients with pseudocysts that are more than 6 weeks old and have a diameter larger than 5 cm because a large proportion of pseudocysts regress during the first 6 weeks after diagnosis and the risks associated with managing the pseudocyst are reduced.
Cystogastrostomy has been performed laparoscopically.
Though less commonly used than drainage procedures into the stomach or jejunum, cystoduodenostomy is effective when a cyst is closely adherent to the duodenum.
Either pancreaticoduodenectomy or distal pancreatectomy, as indicated by anatomy, is effective in treating patients with pseudocysts under ideal circumstances.
Distal pancreatic resection is indicated in patients with a pseudocyst in the body or tail of the pancreas, particularly if associated with multiple small cysts.
Pseudocysts involving the head and uncinate process of the pancreas that are not amenable to internal drainage are rare and may require proximal pancreatic resection, but such resection should be done only as a last resort.
Coran
What are the expected histopathologic findings for congenital hyperinsulinism?
A focal lesion is characterized by a tumor-like proliferation of islet cells that push exocrine elements aside or haphazardly incorporate them.
Unlike insulinomas, the focal lesion retains the lobular architecture of the normal pancreas, and exocrine elements usually remain within the lesion.
The lesions often have irregular borders, and the endocrine cells frequently have enlarged nuclei. Islets outside the lesion appear normal.
Patients with diffuse disease have abnormal islets containing 5% to 10% of cells with enlarged nuclei present throughout the pancreas.
After the surgery, all frozen samples are processed for routine histology and confirmation of findings on the basis of paraffin-embedded sections and insulin immunohistochemistry.
Coran
What is the approach to managing a wandering spleen?
Wandering spleen is characterized by lack of ligamentous attachments to the diaphragm, colon, and retroperitoneum.
The embryologic basis of this is probably related to failure of development of the splenic ligaments from the dorsal mesentery.
Children with this condition most often present with diffuse abdominal pain secondary to torsion and infarction, although they may also present with episodic pain and an abdominal mass.
Although splenectomy is required for infarction, splenopexy is preferred in nonischemic and incidentally detected cases.
Splenopexy has been performed with various techniques including placement in an extraperitoneal pocket, use of Dexon mesh basket, suture splenopexy, and colonic displacement with gastropexy.
Laparoscopic detorsion and splenopexy can be performed with the use of an absorbable mesh bag that is closed around the splenic hilum and then tacked to the diaphragm and posterolateral abdominal wall.
Coran
What are the expected pathologic findings for a resected insulinoma?
Like many endocrine tumors, behavior, not pathology, will determine the malignant potential.
Pancreatic endocrine tumors may be focal or multifocal. so thin sectioning, and careful examination of the specimen is required.
The tumor generally has a pushing border and does not invade surrounding pancreas.
It is composed of monomorphic cells with a salt and pepper chromatin pattern arranged in a gyriform (replicating islets), trabecular, glandular, or solid sheet pattern.
The cells are positive for neuroendocrine markers such as chromogranin and synaptophysin and may demonstrate specific hormone expression (e.g., insulin).
The tumors are classified as either “nonfunctioning” or “functioning,” depending on whether they secrete hormones related to a specific clinical syndrome.
Even nonfunctioning tumors may express immunohistochemically detectable hormone products, so specific immunohistochemical typing is not necessary.
Certain findings may be associated with more aggressive behavior, including large size (>3 cm), necrosis, local and vascular invasion, and high proliferation index, but the only certain indictor of malignancy is the presence of metastasis.
Well-differentiated neuroendocrine tumors are graded from G1 to G3 based on their mitotic index.
Although the tumor in this case showed mild nuclear atypia, the tumor was small and had a low mitotic index.
Sherif
