A brief review regarding the topic of pancreatic neoplasms

1. PANCREATIC NEOPLASMS
-Dr.Anusha
Moderator: Dr.B.Mohan Lal Naik
M.S[Professor]
Dr.Malleswari M.S[Asst]
Dr.Madhava Krishna M.S [Asst]

2.  CLASSIFICATION:
Exocrine Tumours:
-Benign :Benign Cystadenomas
-Malignant :Adenocarcinoma[Ampulla/head]
Cystadenocarcinoma
Endocrine Tumours:
-Insulinomas
-Gastrinomas
-Glucaganomas
-VIPomas

3. ADENOCARCINOMA PANCREAS

4. EPIDEMOLOGY
 Ninth most common cancer diagnosis
 Ranks fourth in cancer deaths each year
 Overall, less than 5% of individuals will survive 5
years beyond diagnosis
 Men are affected slightly more commonly than
women, with a 1.3:1 incidence ratio.
 Risk increases with age beyond sixth decade.

5. RISK FACTORS
 Acquired:
 Smoking
 Chronic pancreatitis
 Obesity
 Diabetes mellitus
 Occupational exposure
 Hereditary :
 Genetic mutations

6. HEREDITARY RISK FACTORS

8. Hereditary Pancreatitis
 PRSS1 – cationic trypsinogen gene
Mutations in this gene are responsible for 80% of
cases of hereditary pancreatitis
--Leads to increased trypsin activity and chronic
inflammation in the pancreas.
 SPINK1gene – codes for serine protease inhibitor
that inhibits active protein.
Mutations in ths gene have been associated with
hereditary pancreatitis

9. Peutz – Jeghers syndrome
 STK11 gene – thought to act as tumour suppressor
gene, with loss of heterozygosity leading to the
development of gastrointestinal tumours.
--Individuals with Peutz Jeghers syndrome are at
higher risk of lung, ovarian, breast, uterine and
testicular cancers.
--Risk of pancreatic cancer in Peutz Jeghers syndrome
is more than 100 times greater than that in unaffected
individuals.

10.  Cystic Fibrosis:
CFTR GENE
Cause remains unclear
Elevated risk of pancreatic cancer is caused by the
chronic inflammatory condition of the pancreas
resulting from a lifetime of thickened secretions and
partial ductal obstruction.

11.  Familial atypical mole and multiple melanoma
syndrome:
CDKN2A GENE
CDKN2A encodes protein p16, which normally
inhibits cell proliferation by binding to cyclin-dependent
kinases.
Mutations of CDKN2A lead to uninhibited cell cycle
activation and proliferation.

12.  Hereditary Breast and Ovarian Cancer:
BRCA2 GENE
Germline mutations of BRCA2 gene lead to an
elevated risk of pancreatic carcinoma
 Lynch Syndrome:
Mismatch repair genes-MLH1,MSH2,MSH6
Lynch syndrome also leads to an increased risk of
pancreatic cancer.
Microsatellite instability noted in colon cancer cells
has also been noted in pancreatic cancer cells from
individuals of Lynch Synndrome.

13.  Familial Adenomatous Polyposis (FAP) :
APC Gene [Adenomatous Polyposis coli]
Individuals affected by familial adenomatous
polyposis are also significantly more likely to develop
pancreatic cancer.
 Familial pancreatitis:
Unknown genetic mutations.
-Defined by families with two or more first degree
relatives wih pancreatic ductal adenocarcinoma that
do not fulfill the criteria of other inherited tumour
syndromes with an increased risk for development of
PDAC.

14. Sporadic Pancreatic Cancer:
--Most cases are sporadic.
--Development of PDAC from Pancreatic intraepithelial
Neoplasia [PanIn].
--Multiple Tumour suppressor genes and oncogenes
have been identified that play a sigificant role in the
pathogenesis of PDAC
PDX1, KRAS2, CDKN2A, P53 and DPC4/SMAD4.

15.  KRAS2 Oncogene:
--Mutation of KRAS2 oncogene is one of the earliest
genetic abnormalities identified in progression of PanIn
to PDAC.
--Activated in more than 95% of pancreatic cancers
and is thought to be the initiating event in
tumourigenesis.
--KRAS2 is activated by point mutation [codon 12, 13,
61] , which causes constitutive activation and loss of
regulation of mitogen activated protein kinase cell
signal transduction.

16.  CDKN2A/P16 :
--CDKN2A encodes protein p16 that binds to cyclin
dependent kinases CDK4, CDK6 resulting in cell cycle
arrest.
--Mutation of CDKN2A and loss of p16 leads to loss of
cell cycle regulation.
 P53 :
--p53 encodes protein p53, which regulates cell
proliferation through cell cycle arrest and proapoptotic
mechanisms. Mutations in p53 has a significant role in
transition from non invasive to invasive tumours.
 DPC4/SMAD4 :
--DPC4 functons as a downstream mediator related to
TGF-Beta,,,therefore loss of DPC4 leads to decreased
inhibition of cell growth and proliferation.

18.  PanIn—defined histologically by progressive
abnormality of the ductal epithelium from columnar
metaplasia through carcinoma in situ.
 PanIn 1A- presence of columnar, mucin producing
ductal epithelium that maintains basally located
homogenous nuclei without atypia.
 PanIn 1B- Development of papillary architecture
 PanIn 2- Progression of simple papillary growth to
nuclear atypia.
 PanIn 3- Enlarged nuclei with nuclear crowding and
loss of polarity and marked cytologic atypia

19. Periampullary Carcinoma:
 It is tumour arising at or near the ampulla.
 It can be
--Adenocarcinoma from the head of pancreas close to
the ampulla-50%
--Tumour from ampulla of vater-30%
--Distal bile duct carcinoma-10%
--Duodenal carcinoma adjacent to ampulla-10%

20. Pathology:
 Gross :
Grayish white scirrhous nodular gritty tumour
More than 3 cm sized tumour shows nodal and
distant spread commonly.
Pancreatic duct may be dilated due to obstruction.
 Microscopy :
It shows malignant cells with variable degree of
differentiation, high mitotic index, severe desmoplastic
reaction with fibrosis.
Shows vascular and lymphatic invasion
High propensity for perineural spread and so to
neural plexus causing back pain.

21. Clinical Presentation:
 Jaundice – obstructive nature; severe progressive;
associated with pruritus. Painless in ampullary
malignancies.
 Pain– right hypochondrium, epigastrium, left
hypochondrium depending on location of tumour.
Back pain may be present due to involvement of
retropancreatic nerves, or pancreatic duct
obstruction, or stasis, disruption of nerve sheath by
tumour. More at night and after intake of food;
relieves on leaning forward.
 Diarrohea, Steatorrhea, Tea coloured urine.
 Loss of appetite and Loss of weight.

22.  New onset Diabetes in an elderly patient with weight
loss may be an early presenting symptom of
pancreatic cancer.
 Left supraclavicular lymphnode enlargement
 Secondaries in Rectovesical pouch [Blumer Shelf]
 Periumbilical Lymphadenopathy [Sister Mary Joseph
Nodules]
 Gallbladder may be palpable, nontender, moving
with respiration.
 Liver enlargement– Secondaries
 Ascites

23. Investigations:
 Routine Surgical Profile
 Liver Function Tests:
1]Serum bilirubin – Direct component increased
2]Serum Albumin – Decreased with altered A:G ratio.
3]Prothrombin time is increased.
4]Serum Alkaline Phosphatase is increased

24.  Spiral CT -- imaging study of choice
Allows an accurate determination of the level of
biliary obstruction, size of tumour, retroperitoneal
lymphnodes.
Three phase CT-scan (noncontrast, arterial and portal
venous) with 3 mm slices and coronal and three
dimensional reconstruction should be routine.
--Pancreatic adenocarcinoma is typically seen as
hypoattenuating lesion during portal venous phase of
imaging.
 ERCP -- assessment of jaundiced patient
-ability to perform a biopsy
-ability to palliate jaundice

25.  Endoscopic Ultrasound --
Evaluation of peritumoural vasculature and regional
lymph nodes
Endoscopic Ultrasound guided biopsy/ FNAC.
For the identification of small tumours that do not
appear on CT scans and for the delineation of more
clearly suspicious lesions smaller than 2 cms
 MRCP - detailed assessment of luminal
pancreatobiliary anatomy.
Non invasive ; no risk of inciting pancreatitis;
provides three dimensional reconstruction of the ductal
system.

26. STAGING :
 Based on American Joint Committee on Cancer
tumour, Node, Metstasis [TNM ] system.
 Accomplished typically based on Endoscopic
ultrasound guided FNAC, accurately by multidetector
CT scanning of the abdomen and pelvis with three
phase administration of contrast material and three
dimensional reconstruction.

28.  Depending on CT imaging, tumours are classified
into
-Resectable
-Borderline resectable
-Unresectable
 Individuals with stages IA to IIB tumours- tumours
confined to pancreas or peripancreatic tissue without
evidence of celiac artery or SMA involvement and no
evidence of metastasis– are considered as
candidates for surgical resection.

29.  Resectable tumours are defined as confined to the
pancreas with no evidence of SMV or portal vein
involvement and a preserved fat plane sorrounding the
SMA and celiac artery branches including hepatic artery.
 Borderline resectable tumours are defined as tumours
that exhibit one of the following characteristics:
-severe unilateral or bilateral SMV- portal impingement
-less than 180 degree tumour abutment on the SMA.
-abutment or encasement of hepatic artery, if
recconstructible.
-SMV occlusion, if of a short segment and
reconstructible.
 Unresectable tumours are those that exhibit metastasis,
ascites or vascular involvement .

30. Staging Laparoscopy
 To reduce the frequency of nontherapeutic
laparotomy for patients with unsuspected metastatic
or locally advanced unresectable disease at the time
of surgery.
 Indications:
-Large tumours of size > 3 cm
-Significantly elevated CA19-9 level (>100U/ml)
-Uncertain findings on CT
-Body or tail tumours.

31. Preoperative Preparation:
 Correction of anemia.
 Adequate hydration is important in order to prevent
dehydration postoperatively.
 Replenishment of glycogen store.
 Mannitol should be given intravenously 3 days prior
to surgery to flush the kidney—preventing
hepatorenal syndrome postoperatively.
 Antibiotics one day prior to surgery.
 TPN may be required preoperatively which is also
continued postoperatively.
 Pulmonary function studies and respiratory
physiotherapy

32. Treatment:
 Surgery for tumours of the head of the pancreas:
---Pancreaticoduodenectomy
WHIPPLE’S PROCEDURE.
 Surgery for tumours of the Body and Tail of the
Pancreas:
---Distal pancreatectomy and en bloc spleenectomy.

33.  PANCREATICODUODENECTOMY-Steps:
-Cattell-Braasch manuever
-Kocher manuever
-Portal dissection
-Stomach transection
-Jejunum transection
-Pancreas transection and retroperitonel dissection.

34. Reconsructions
-End to side
Pancreaticojejun
stomy
-End to side
Hepaticojejunost
omy
-End to side
Gastrojejunosto
my(antecolic)

35.  Structures removed in Pancreaticoduodenectomy:
-Distal stomach
-Head of the pancreas
-Duodenum
-CBD
-Gall Bladder
-Proximal Jejunum
-Regonal Lymphatics

36. Surgery for tumours involving body and tail
of the pancreas:
 These tumours are rarely resectable at the time of
presentation.
 For resectable tumours --- Distal Pancreatectomy
and En bloc Spleenectomy should be performed.

37. Outcomes:

38.  Pancreatic fistula is the major source of morbidity
after the whipple operation.
 Pancreatic Fistula defined as output via an
intraoperatively placed drain of any measurable
volume on or after postoperative day 3, with amylase
>3 times normal serum value.
 Most fistulas are controlled by drainage catheters
placed at the time of surgery and require no
additional intervention
 Uncontrolled fistulas require an additional drain
placement or completion pancreatectomy to prevent
further abdominal contamination.

39. Extent of Lymphadenectomy:
 In addition to peripancreatic, portal and pyloric
lymphnodes, extended lymphadenectomy
includes retrieval of hilar and retroperitoneal
lymph nodes, extending from celiac origin to the
level of the inferior mesenteric artery and
including all tissue between the renal hilum
laterally.

40. Adjuvant therapy
 The current guidelines recommend GEMCITABINE
or 5-FLUOROURACIL or in combination with 5- FU
based chemoradiation as adjuvant treatment after
resection.
 For Metastatic carcinoma—FOLFIRINOX
-combinaton of 5-FU, Oxaliplatin, Irinotecan and
Leucovorin used as neoadjuvant regimen of choice in
patients with borderline resectable tumours.

41. Recent Advances:
 EGFR inhibitors:
-ERLOTINIB & CETUXIMAB targets EGFR
dependent pathways
-approved for treatment of unresectable tumours.
 Vascular endothelial growth factor inhibitor--
BEVACIZUMAB

42. Palliative Therapy:
 Biliary Obstruction:
-ERCP with metal stent placement
-Surgical biliary-enteric Bypass (Roux-en-Y
Hepaticojejunostomy)
 Gastric Outlet Obstruction:
-Endoscopic luminal stenting.
-Double Bypass-Roux-en-Y-Hepaticojejunostomy and
Gastrojejunostomy
 Pain relief:
-NSAIDS or long acting opiods
-Celiac nerve block
-Neurolysis.

43. Cystic Neoplasms of Pancreas

44.  Second most common exocrine pancreatic
neoplasm next to adenocarcinoma.
 Types
-Mucinous
-Serous
-Intraductal Papillary Mucinous Neoplasms

45. MUCINOUS CYSTIC NEOPLASM
 Most common cystic neoplasms of the
pancreas.
 Most commonly in Young women, Men are rarely
affected.
 Mean age at presentation is Fifth decade.
 Typically found in the body and tail of the
pancreas

46. • Contain mucin-producing
epithelium
• Presence of mucin-rich cells and
ovarian-like stroma
• CT scan –solitary cyst with fine
septations, surrounded by a rim
of calcification.
• Predictors of malignancy
-Eggshell calcification, larger
tumor size,mural nodule on cross-
sectional imaging.

47.  EUS and cyst fluid analyses demonstrate
--mucin-rich aspirate
--high CEA levels (>192 ng/mL)
--low levels of amylase
 Standard treatment - Pancreatic resection and
adjuvant systemic chemotherapy after resection.

48. SEROUS CYSTIC NEOPLASM
 Predilection for the head of the pancreas
 Vague abdominal pain and less frequently with
weight loss and obstructive jaundice
 Gross--Large , well circumscribed masses.
 Microscopy - multiloculated, glycogen-rich small
cysts.
 CT Scan-
Central calcification, with radiating septa giving the
sunburst appearance (10-20%)

49. Treatment:
 Large (>4 cm) or rapidly growing, symptomatic
lesion--- Treatment is Resection
 Small (<4 cm) --asymptomatic and can be kept for
observation.

50. Intraductal Papillary Mucinous Neoplasms:
 Manifests in Sixth to seventh decade of life.
 Commonly involves head of pancreas.
 Wide spectrum of epithelial changes ranging from
benign adenoma, borderline, carcinoma insitu, and
invasive adenocarcinoma.
 Types-
--Side branch or branch duct IPMN
--Main duct IPMNs
--Mixed -type IPMNs

51. Branch duct intraductal papillary mucinous
neoplasms:
 Involves dilation of the pancreatic duct side branches
that communicate with but do not involve the main
pancreatic duct.
 Focal (involving a single side branch) or multifocal.
 Risk of malignant transformation directly related to
the size of the cystic dilation.
 Others - mural nodules or general thickening of the
cyst wall symptoms like jaundice, pain, and diabetes.

52.  Small (<1 cm) IPMNs:-
--Surveillance with CT or MRI in 1 year
 Asymptomatic cysts ,1 -3 cm:-
--Imaging at 6 months followed by annual evaluation
if no change in size.
 Cysts larger than 3 cm:-
--Surgical resection (Partial pancreatectomy)
 Risk of invasive malignancy- 10% to 15%

55. Main duct intraductal papillary
mucinous neoplasm:
 Abnormal cystic dilation of the main pancreatic duct
with columnar metaplasia
 Endoscopy –thick mucinous secretions oozing from
patulous papilla
 May be focal or diffuse
 30% to 50% risk of harbouring invasive pancreatic
cancer at the time of presentation.

56.  Treatment- Surgical resections as there is risk of
malignant transformation.
 Predictors of malignancy-
--Jaundice
--Elevated serum alkaline phosphatase
--Mural nodules
--Diabetes
--Main pancreatic duct diameter of 7 mm
 Elevation of the CEA level is not predictive of
invasive malignancy.

57.  CT scan –
Dilated main pancreatic duct, cysts of varying sizes
and possibly mural nodules.
 MRCP--localization of mural nodules and
pretreatment classification of suspected side branch
or main duct types of IPMN
 Aspirated fluid is typically viscous and clear, contains
mucin and columnar mucinous cells with variable
atypia
 Elevated CEA level (>192 ng/mL)

58. Mixed type intraductal papillary mucinous
neoplasms
 Side branch IPMN that has extended to involve the
main pancreatic duct.
 Risk of invasive malignancy at the time of
presentation (30% to 50%)
 Surgical resection is indicated for the treatment.

60. Tumours of endocrine pancreas

61.  Endocrine tumours
 Insulinoma (β cells)
 Gastrinoma (G cells)
 Glucagonoma (α cells)
 Vipoma—Pancreatic cholera (Verner-Morrison
syndrome)
 Somatostatinoma ---(S cells) δ cells

62. INSULINOMAS
 Most common functioning tumor
 They arise from Beta cells of pancreas.
 Equal distribution in the head, body, and tail.
 97% are located in the pancreas, remaining 3% are
located in the duodenum, splenic hilum, or
gastrocolic ligament
 Whipple’s triad
--Fasting-induced neuroglyopenic symptoms of
hypoglycemia
--Low blood glucose levels (40 to 50 mg/dL),
--Relief of symptoms after the administration of
glucose.

63.  Clinical Features:
--Abdominal discomfort, tremors, sweating, hunger,
dizziness, diplopia, hallucinations. Later epilepsy and
unconsciousness.
--They are usually over weight. Weight gain is
common due to overeating.
--Permanent neurological deficits can occur with
behavioural changes.

64. Investigations:
• 72 hour fasting
test
- High level of serum
insulin (>5 μU/mL)
-Insulin-to-glucose
ratio higher than 0.3
-C peptide levels
higher than 1.2
μg/mL
• CECT or MRI--
Hyperattenuating
lesions because of
their rich vascular
supply.

65. Treatment
 Enucleation commonly, often distal pancreatectomy
 Diazoxide, beta blockers, phenytoin, verapamil,
steroids, growth hormone to control hypoglycaemia
 Octreotide decreases the insulin secretion
 Calcium channel blockers
 Streptozotocin whenever secondaries are present in
liver or elsewhere
 Enucleation of all tumours.
 Often distal pancreatectomy is required (spleen; tail
and body of the pancreas are removed) 90% are
curable.

66. GASTRINOMAS
 They arise from non-beta cells (G cells) of the
pancreas, which secretes high levels of gastrin.
 It is 2nd most common endocrine pancreatic tumour.
 It is the commonest endocrine pancreatic tumour
seen in MEN I syndrome. In MEN II syndrome lesion
is often seen in duodenum (30%).
 It is common in males.
 Common in gastrinoma triangle (Passaros triangle)

67. Gastrinoma triangle
(90%)
-The cystic duct CBD
junction
-The JUNCTION
between the second
and third portions of the
duodenum
-Junction between the
neck and body of the
pancreas

68.  Half of them are multiple and malignant (50%).
 It causes severe, multiple peptic ulcers in the
stomach,
 duodenum and jejunum.
 It is due to hypergastrinaemia causing high levels of
acid secretion.
 Other features are diarrhoea, steatorrhoea,
hypokalaemia.
 It causes ZES type II.
 When malignant commonly present with secondaries
in liver(80%)/lymph nodes/lungs or bones.

69. Investigations:
 Presence of hypergastrinemia in the presence of
increased secretion of gastric acid.
 An elevated serum gastrin level coupled with a pH
lower than 2 in the gastric aspirate
 Fasting levels of gastrin - higher than 1000 pg/mL
(upper limit of normal of 100 pg/mL)
 An increase of more than 200 pg/mL in the gastrin
value after administration of secretin

70. Treatment:
 60% are curable.
 Enucleation of tumours.
 Distal pancreatectomy.
 Pancreaticoduodenectomy.
 Subtotal pancreatectomy.
Often total gastrectomy may be required.

71. GLUCAGANOMAS
 Arise from α cells of pancreas.
 Common in body and tail of pancreas.
 It is common in females.
 It attains large size of 5-10 cm.
 It is commonly sporadic. 17% associated with MEN
type II syndrome.
 It is commonly malignant (80%). 80% spreads to
liver.

72. Clinical features:
 Necrolytic migratory erythema (65%).
 Diabetes (90%).
 Diarrhoea and weight loss.
 Stomatitis.
 Anaemia and features of amino acid defi ciency.

73. Investigations:
 MRI, CT scan.
 Endosonography.
 Angiogram.
 Increased serum glucagon level. Fasting glucagon
level more than 50 p mol/litre is diagnostic.
 Treatment
Distal Pancreatectomy
Dacarbazine is specially effective in Glucaganomas.

74. VIPOMAS
 Arising from D2 cells of pancreas
 Watery diarrhoea, hypokalaemia, achlorohydria
(WDHA syndrome)
 Also called as pancreatic cholera or Verner-
Morrison syndrome, weak—tea syndrome
 Usually malignant
 Secretes vasointestinal polypeptide > 150 pg/ml
 Common in body and tail—solitary
 Distal pancreatectomy is the treatment of choice
 Prednisolone controls the diarrhoea
 Octreotide is useful

75. SOMATOSTATINOMAS
 Usually solitary and 85% are larger than 2 cm.
 Mostly at head of pancreas
 Ninety percent are malignant
 Steatorrhea , diabetes mellitus, hypochlorhydria, and
gallstones
 Fasting somatostatin level higher than 14 mol/liter
 Associated with von Recklinghausen’s disease and
pheochromocytomas.
 Treatment remains the resection of the tumour.