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1. Neoplasms of the pancreas
Yonas Ademe
August, 2017
1

2. Neoplasms of the Endocrine
Pancreas
2

3. Introduction
• Neoplasms of the endocrine pancreas are relatively
uncommon but do occur with enough frequency
• The cells of the endocrine pancreas, or islet cells,
originate from neural crest cells
– Multiple endocrine neoplasia (MEN) syndromes occur
when these cells cause tumors in multiple sites
• Some pancreatic endocrine neoplasms are
functional, secreting peptide products that produce
interesting clinical presentations
3

4. Cont.
• Unfortunately, most pancreatic endocrine
tumors are malignant, but the course of the
disease is far more favorable than that seen
with pancreatic exocrine cancer
• The key to diagnosing these rare tumors is
recognition of the classic clinical syndrome
– Confirmation is achieved by measuring serum levels
of the elevated hormone
4

5. Cont.
• As with pancreatic exocrine tumors, the initial
diagnostic imaging test of choice for pancreatic
endocrine tumors is a multidetector CT scan
– Neuroendocrine tumors of the pancreas often enhance
with contrast
• EUS
• Radionuclide scanning
– In contrast to pancreatic exocrine tumors, many of the
endocrine tumors have somatostatin receptors that
allow them to be detected by a radiolabeled octreotide
scan
• A radioactive somatostatin analogue is used
5

6. Cont.
• The goals of surgery range from complete
resection, often accomplished with
insulinomas, to controlling symptoms with
debulking procedures
6

7. Insulinoma
• Unlike most endocrine pancreatic tumors, the
majority (90%) of insulinomas are benign and
solitary, and only 10% are malignant
• 90% of insulinomas are sporadic, and 10% are
associated with the MEN1 syndrome
– Insulinomas associated with the MEN1 syndrome
are more likely to be multifocal and have a higher
rate of recurrence
7

8. Cont.
• Insulinomas are the most common functional
pancreatic endocrine neoplasms and present
with a typical clinical syndrome known as
Whipple’s triad
– Symptomatic fasting hypoglycemia
• Patients can present with a profound syncopal episode
– Other: palpitations, trembling, diaphoresis, confusion or
obtundation, and seizure
– A documented serum glucose level <50 mg/dL
– Relief of symptoms with the administration of glucose
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9. Cont.
• Laboratory
– A low blood sugar
– Serum insulin levels are elevated
– C-peptide levels should also be elevated
• Excess insulin production leads to excess C-peptide
• Imaging
– CT scan
– EUS
• It is the most sensitive imaging method for all islet cell tumors
9

10. Cont.
• Insulinomas are typically cured by simple
enucleation
– However, tumors located close to the main
pancreatic duct and large (>2 cm) tumors may
require a distal pancreatectomy or
pancreaticoduodenectomy
10

11. Gastrinoma
• Endocrine tumor that secretes gastrin, leading to
acid hypersecretion and peptic ulceration –
Zollinger-Ellison syndrome
• In 70% to 90% of patients, the primary gastrinoma
is found in Passaro’s triangle, an area defined by a
triangle with points located at the junction of the
cystic duct and CBD, the second and third portion
of the duodenum, and the neck and body of the
pancreas
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12. Cont.
12

13. Cont.
• Many patients with ZES present with
abdominal pain, PUD, and severe esophagitis
– Ulcers often fail to respond to antacids
• The diagnosis of ZES is made by measuring the
serum gastrin level plus imaging
• It is important to rule out MEN1
13

14. Glucagonoma
• Diabetes in association with dermatitis should raise the
suspicion of a glucagonoma
• They are more often in the body and tail of the pancreas
and tend to be large tumors with metastases
• The classic necrolytic migratory erythema manifests as
cyclic migrations of lesions with spreading margins and
healing centers typically on the lower abdomen,
perineum, perioral area, and feet
– Thought to be caused by low levels of amino acids
• Patients also complain of an enlarged, sensitive tongue
• Glucagon is a catabolic hormone, and most patients
present with malnutrition
14

15. Cont.
• The diagnosis is confirmed by measuring serum
glucagon levels
• Debulking operations are recommended in good
operative candidates to relieve symptoms
15

16. Somatostatinoma
• Most of these tumors originate in the proximal
pancreas or the pancreatoduodenal groove, with
the ampulla and periampullary area as the most
common site (60%)
• Because somatostatin inhibits pancreatic and
biliary secretions, patients present with gallstones
due to bile stasis, diabetes due to inhibition of
insulin secretion, and steatorrhea due to inhibition
of pancreatic exocrine secretion and bile secretion
16

17. Cont.
• Diagnosis is confirmed by elevated serum
somatostatin levels
• Although most reported cases of
somatostatinoma involve metastatic disease, an
attempt at complete excision of the tumor and
cholecystectomy is warranted in fit patients
17

18. VIP-Secreting Tumor (VIPoma)
• A pancreatic endocrine neoplasm with severe
intermittent watery diarrhea leading to
dehydration, and weakness from fluid and
electrolyte losses
– Large amounts of potassium are lost in the stool
18

19. Neoplasms of the Exocrine
Pancreas
19

20. Introduction
• Overall, pancreatic cancer has the worst
prognosis of all malignancies with a 5-year
survival rate of only 6%
• The incidence of pancreatic cancer continues to
increase, perhaps related to the increased
incidence of risk factors such as obesity and
diabetes
20

21. Risk factors
• Old age (>60 years old)
• M > F
• Black race
• Family history
• Cigarette smoking
• Diet
– As in other GI cancers, diets high in fat and low in fiber, fruits, and vegetables are
thought to be associated with an increased risk of pancreatic cancer
• DM
– Pre-existing type 2 diabetes increases the risk for development of pancreatic
cancer by about twofold
– Glucose intolerance is present in 80% of patients with pancreatic cancer, and
approximately 50% have overt diabetes
– The new onset of diabetes can be an early manifestation of otherwise occult
pancreatic cancer
• Chronic pancreatitis
• Coffee and alcohol consumption have been investigated as possible risk
factors, but the data are inconsistent 21

22. Genetics
• K-ras oncogene
– Currently thought to be the most commonly
mutated gene in pancreatic cancer, with
approximately 90% of tumors having a mutation
• Other
– HER-2/neu
– Gp53
– P16
– DPC4
22

23. Pathology
• About 2/3rd of pancreatic adenocarcinomas
arise within the head or uncinate process of the
pancreas; 15% are in the body, and 10% in the
tail, with the remaining tumors demonstrating
diffuse involvement of the gland
• Tumors in the pancreatic body and tail are
generally larger at the time of diagnosis, and
therefore, less commonly resectable
23

24. Cont.
• Tumors in the head of the pancreas are typically
diagnosed earlier because they cause OJ
• Ampullary carcinomas, carcinomas of the distal bile
duct, and periampullary duodenal
adenocarcinomas present in a similar fashion to
pancreatic head cancer but have a slightly better
prognosis, probably because early obstruction of
the bile duct and jaundice leads to the diagnosis
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25. Cont.
• Systematic histologic evaluation of areas
surrounding pancreatic cancers has revealed
the presence of precursor lesions that have
been named pancreatic intraepithelial
neoplasia
– 3 stages of pancreatic intraepithelial neoplasia have
been defined
25

26. Cont.
• In addition to ductal adenocarcinoma, which
makes up about 75% of nonendocrine cancers
of the pancreas, there are a variety of less
common types of pancreatic cancer
– Acinar cell carcinoma
– Adenosquamous carcinoma
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27. WHO classification of primary tumors
of the exocrine pancreas
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28. Clinical features
• The pancreas is situated deep within the abdomen,
and the early symptoms of pancreatic cancer often
are too vague to raise suspicion of the disease
– Ultimately, the majority of patients present with pain
and jaundice
• On physical examination
– Weight loss is evident (a sign of advanced disease)
– Skin is icteric
– distended GB is palpable in about one-fourth of patients
28

29. Cont.
• Although it is often taught that carcinoma of the
pancreas presents with painless jaundice (to help
distinguish it from choledocholithiasis), this
aphorism is not accurate
– Most patients do experience pain as part of the
symptom complex of pancreatic cancer, and it is
often the first symptom
• The pain associated with pancreatic cancer is usually
perceived in the epigastrium but can occur in any part of
the abdomen, and often, but not always, penetrates to the
back
29

30. Cont.
• A low threshold for ordering a CT scan with
“pancreatic protocol” should be maintained for
elderly patients with unexplained, persistent,
although vague, abdominal pain
– New-onset diabetes in an elderly patient, especially
if combined with vague abdominal pain, should
prompt a search for pancreatic cancer
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31. Diagnosis
• The most critical deficit in the ability to treat
pancreatic cancer effectively is the lack of tools for
early diagnosis
– 8% of pancreas cancer cases are diagnosed while the
cancer is still confined to the primary site (localized
stage)
– 27% are diagnosed after the cancer has spread to
regional lymph nodes
– 53% are diagnosed after the cancer has already
metastasized (distant stage)
– For the remaining 12%, the staging information was
unknown
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32. Cont.
• Laboratory
– LFT
• Direct hyperbilirubinemia and elevated ALP
• Prolonged PT
– Tumor markers
• CA19-9
– Elevated in about 75% of patients with pancreatic cancer
– However, CA19-9 is also elevated in about 10% of patients with
benign diseases of the pancreas, liver, and bile ducts
» It is thus neither sufficiently sensitive nor specific to allow
an early diagnosis of pancreatic cancer
32

33. Cont.
• Imaging
– Abdominal ultrasound
• A reasonable first diagnostic imaging study In patients
presenting with jaundice
• Demonstration of cholelithiasis and bile duct dilation suggests
a diagnosis of choledocholithiasis, and the next logical step
would be ERCP to clear the bile duct
• In the absence of gallstones, malignant obstruction of the bile
duct is likely, and a CT scan is the next imaging modality
– CT scan (Contrast-enhanced)
• First test for patients suspected of having pancreatic cancer
who present without jaundice
• Current diagnostic and staging test of choice for pancreatic
cancer
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34. Cont.
• Cont.
– EUS
– MRI
• Currently provides essentially the same information as
CT
– PET
• May help distinguish chronic pancreatitis from
pancreatic cancer
– Diagnostic laparoscopy
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35. Staging
• TNM staging
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36. Palliative surgery
• For the 85% to 90% of patients with pancreatic
cancer who have disease that precludes surgical
resection, appropriate and effective palliative
treatment is critical to the quality of their
remaining life
• Because of the poor prognosis of the disease, it is
not appropriate to use invasive and toxic regimens
in patients with extremely advanced disease and
poor performance status
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37. Cont.
• In general, there are three clinical problems in
advanced pancreatic cancer that require
palliation:
– Pain
• The mainstay of pain control is oral narcotics
– Jaundice
– Duodenal obstruction
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38. Cont.
• Pain
– Oral narcotics
• The mainstay of pain control
– Celiac plexus nerve block
• It can control pain effectively for a period of months,
although the procedure sometimes needs to be
repeated
• Invasion of retroperitoneal nerve trunks accounts for
the severe pain experienced by patients with advanced
pancreatic cancer
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39. Cont.
• Jaundice
– The most troublesome aspect for the patient is the
accompanying pruritus
• Other: cholangitis, coagulopathy, digestive symptoms, and
hepatocellular failure
– Options
• Endoscopic stents
– Recurrent obstruction and cholangitis is more common with stents and
results in inferior palliation
– Not as durable as a surgical bypass
• Biliary bypass
– Choledochojejunostomy
» It is the preferred approach
– Choledochoduodenostomy
» Felt to be unwise because of the proximity of the duodenum to tumor
– Cholecystojejuno/doudenostomy
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40. Cont.
• Duodenal obstruction
– It is usually a late event in pancreatic cancer and
occurs in only about 20% of patients
– Gastrojejunostomy
• It should be placed dependently and posterior along the
greater curvature to improve gastric emptying, and a
vagotomy should not be performed
40

41. Cont.
• If an initial diagnostic laparoscopy reveals a
contraindication to the Whipple procedure, such as
liver metastases, it is not appropriate to perform a
laparotomy simply to create a biliary bypass
– In such a patient, it is better to place an endoscopic
stent
• In contrast, if a laparotomy has already been
performed as part of the assessment of
resectability and the Whipple procedure is not
possible, a surgical bypass is usually performed
41

42. Cont.
• Some surgeons use a loop of jejunum with a
jejunojejunostomy to divert the enteric
stream away from the biliary-enteric
anastomosis
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43. Cont.
• Triple bypass
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44. Cont.
• Others use a Roux-en-Y limb with the
gastrojejunostomy located 50 cm downstream
from the hepaticojejunostomy
– Advantages
• Ease with which it will reach up to the hepatic hilum
• Probable decreased risk of cholangitis
• Easier management of biliary anastomotic leaks
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45. Cont.
• Roux-en-Y anastomosis
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46. Cont.
• Whether performing both a biliary and enteric
bypass or just a biliary bypass, the jejunum is
brought anterior to the colon, if possible, rather
than retrocolic, where the tumor potentially
would invade the bowel sooner
46

47. Palliative Chemotherapy and Radiation
• Patients with locally advanced unresectable
disease are treated with chemotherapy and
possibly radiation
• Patients with Stage IV metastatic disease are
treated with systemic chemotherapy
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48. Surgical Resection with curative intent:
Pancreaticoduodenectomy
• In a patient with appropriate clinical and/or imaging
indications of pancreatic cancer, a tissue diagnosis
before performing a pancreaticoduodenectomy is not
essential
– Although percutaneous CT-guided biopsy is usually safe,
complications such as hemorrhage, pancreatitis, fistula,
abscess, and even death can occur
– The other problem with preoperative or even intraoperative
biopsy is that many pancreatic cancers are not very cellular
and contain a significant amount of fibrous tissue, so a
biopsy may be misinterpreted as showing chronic
pancreatitis if it does not contain malignant glandular cells
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49. Cont.
• Pancreaticoduodenectomy can be performed through a
midline incision from xiphoid to umbilicus or through a
bilateral subcostal incision
• The initial portion of the procedure is an assessment of
resectability
– Findings contraindicating resection
• Liver metastases (any size)
• Celiac lymph node involvement
• Peritoneal implants
• Hepatic hilar lymph node involvement
– Findings not contraindicating resection
• Invasion at duodenum or distal stomach
• Involved peripancreatic lymph nodes
• Involved lymph nodes along the porta hepatis
49

50. Cont.
• Either the duodenum is divided 2 cm distal to
the pylorus (which defines the procedure as a
pylorus-preserving pancreatico-duodenectomy,
or PPPD) or the antrum is divided, as classically
described by Whipple
• Whipple: radical pancreaticoduodenectomy
followed by pancreaticojejunostomy,
gastrojejunostomy and choledochojejunostomy
50

51. Cont.
51

52. Complications of
Pancreaticoduodenectomy
• The most common causes of death are sepsis,
hemorrhage, and cardiovascular events
• Postoperative complications are very common,
and include:
– Delayed gastric emptying
– Pancreatic fistula
– Hemorrhage
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53. Cont.
• Delayed gastric emptying
– It is common after pancreaticoduodenectomy
– It is treated conservatively as long as complete GOO
is ruled out by a contrast study
• In the acute phase, IV erythromycin may help but the
problem usually improves with time
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54. Cont.
• Pancreatic fistula
– Incidence varies from 0% to 40% depending on the definition
of fistula
– Preventive strategies
• Modifications of the anastomotic technique (end-to-side or end-to-
end, duct-to-mucosa, or invaginated)
• The use of jejunum or the stomach for drainage
– Observational clinical studies reported superiority of pancreaticogastrostomy
over pancreaticojejunostomy
• The use of pancreatic duct stents
• The use of octreotide
– If not combined with a biliary leak, pancreatic fistula,
although serious, can usually be managed conservatively
• In about 95% of cases, reoperation is not indicated and prolonged
drainage results in spontaneous closure of the fistula
54

55. Cont.
• Hemorrhage
– It can occur either intraoperatively or postoperatively
– Intraoperative hemorrhage typically occurs during the
dissection of the portal vein
– Postoperative hemorrhage can occur from:
• Inadequate ligature of any one of numerous blood vessels
during the procedure
• Due to digestion of retroperitoneal blood vessels due to a
combined biliary-pancreatic leak
• A stress ulcer, or later, a marginal ulcer (uncommonly)
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56. Outcome after
Pancreaticoduodenectomy
• Although pancreaticoduodenectomy may be
performed with the hope of the rare cure in
mind, the operation more importantly provides
better palliation than any other treatment, and
is the only modality that offers any meaningful
improvement in survival
– If the procedure is performed without major
complications, many months of palliation are
usually achieved
56

57. Cont.
• Survival rates vary according to the stage of disease at
diagnosis, and most patients have evidence of locally and
sytemically advanced disease at the time of surgery
• The tumor tends to recur locally with retroperitoneal and
regional lymphatic disease
• Median survival after pancreaticoduodenectomy is about
22 months
– Even long-term (5-year) survivors often eventually die due to
pancreatic cancer as late recurrence is common
57

58. Postoperative Surveillance
• Recurrence after successful resection usually
manifests as hepatic metastases
• Patients are monitored with frequent physical
examinations, laboratory tests (including CA19-9),
and CT scans
• Surgical therapy for recurrent disease is usually
reserved for patients who remain reasonable
operative candidates who develop symptomatic
gastric outlet or bowel obstruction
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59. Adjuvant Chemoradiotherapy
• Controversial for years
– Nevertheless, pending further study, it is typical in
the United States for patients with acceptable
functional status to receive some form of adjuvant
chemotherapy and radiotherapy after surgery
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60. Neoadjuvant chemoradiotherapy
• Potential advantages
– It may decrease the tumor burden at operation,
increasing the rate of resectability
– It avoids the risk that adjuvant treatment is delayed
by complications of surgery
– It allows patients with occult metastatic disease to
avoid the morbidity of pancreatic resection
• Many studies recommend it
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61. Diagnostic and treatment algorithm
61

62. Ampullary and Periampullary
Cancer
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63. Introduction
• Ampullary cancers need to be distinguished from
periampullary cancers
– Periampullary cancer includes tumors arising from the
distal bile duct, duodenal mucosa, or pancreas just
adjacent to the ampulla
– The term ampullary cancer is more specific and is
reserved for tumors that arise at the ampulla
• The ampulla is the junction of the biliary and pancreatic ducts
within the duodenum
• Based on their location, ampullary cancers are usually detected
relatively early due to the appearance of jaundice and have a
more favorable prognosis
– A 10-year survival of about 35%
63

64. Cont.
• The ampulla of Vater is lined by an epithelial layer that
transitions from pancreatic and biliary ductal epithelium to
duodenal mucosal epithelium
– Ampullary adenocarcinomas can therefore have an intestinal
and/or pancreaticobiliary histologic morphology, with the former
having a better prognosis
• The difference in survival between ampullary and pancreatic
adenocarcinoma of the pancreas is not entirely explained by
an earlier presentation and lower incidence of lymph node
metastases
– There are probably biologic, particularly molecular, differences
• Benign tumors such as ampullary adenomas can also
originate at the ampulla
64

65. Cystic Neoplasms of the Pancreas
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66. Introduction
• Cystic neoplasms of the pancreas may be more
frequent than previously recognized and are
being identified with increasing frequency as
the use of abdominal CT scanning has increased
• Most of these lesions are benign or slow
growing, and the prognosis is significantly
better than with pancreatic adenocarcinoma
66

67. Cont.
• Radiologic features
– Size of the lesion
– Growth rate
– Density of the lesion
– Characteristics of the wall such as nodules
– Septations
– Calcifications
67

68. Cont.
• EUS-guided FNA and analysis of cyst fluid or
ERCP provide useful additional information to
guide clinical decision making besides clinical
and radiological clues
– Cysts that contain thick fluid with mucin, elevated
CEA, or atypical cells must be treated as potentially
malignant
68

69. Pseudocysts
• The most common cystic lesion of the pancreas is
the pseudocyst, which, of course, has no epithelial
lining and is a non-neoplastic complication of
pancreatitis or pancreatic duct injury
• The diagnosis is usually straightforward from the
clinical history
• Analysis of pseudocyst fluid would reveal a high
amylase content
69

70. Cont.
• The danger comes in mistaking a cystic
pancreatic neoplasm for a pseudocyst and
incorrectly draining a cystic neoplasm into the
GI tract rather than resecting the neoplasm
– For this reason, biopsy of the pseudocyst wall is a
common step in the management of pancreatic
pseudocysts
70

71. Other cystic lesions
• Cystadenoma (serous or mucinous)
• Cystadenocarcinoma
• Intraductal Papillary Mucinous Neoplasm
• Cystic degeneration typical ductal
adenocarcinoma
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72. End!
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