3. TUMOURS OF THE PANCREAS
The tumors of the pancreas can be -
A. Non-Endocrine neoplasms
B. Endocrine neoplasms
4. NON-ENDOCRINE NEOPLASMS:
Benign non-endocrine neoplasms of pancreas. Includes:-
(adenoma, cystadenoma, lipomas, fibromas, haemingoma,
lymphangioma and neuromas).
• They are extremely rare and no clinical significance unless they
become palpable or give pressure to adjacent structures and
• Can be solid or cystic or both.
• The diagnosis should be made after exclusion of more frequent
5. Malignant non-endocrine neoplasms. The most
(Exocrine cell of pancreas )
6. ENDOCRINE NEOPLASMS:
These are less common than non-endocrine tumours and
generally benign and sometimes multiple. They includes:
- Vipomas (Vasoactive Intestinal Polypeptide)
• Pancreatic carcinoma is a relatively common tumor with an
incidence of 7.6 per 100.000 per year in Western-Europe.
• 9th MC cancer diagnosis
• 4th in cancer deaths each year.
• The majority of pancreatic cancers (85%) are adenocarcinoma of
ductal origin (PDAC).
• And the term "pancreatic cancer" is sometimes used to refer only
to that type.
• It is more common in men (men:woman 1.3:1)
• It comprises about 2.5 % of all newly diagnosed tumors and 5% of
• 5 year survival is <5%
• In spite of the limited tumor size the majority of pancreatic head
cancers (80%) are not eligible for resection at the time of diagnosis.
9. Risk factors for pancreatic carcinoma
• Inherited susceptabilityEstablished
• c/c pancreatitis
• DM type 2
• Obesity ( 3 times , BMI >35)
• Physical inactivity
• Certain pesticides
• High CHO/sugar intake.
10. Risk factors
• Older age -cases before age 40 are uncommon
• Mean 72
• Common in African Americans, though incidence in Africa is
• low socioeconomic status
• Ashkenazic jewish heritage are assoc increased risk of PC
• There is Association b/w risk of pancreatic cancer , H.pylori
colonization and ABO blood groups.
• Cirrhosis & c/c pancreatitis
• A high fat or cholesterol diet, & prior cholecystectomy.
– processed meat, red meat, and meat cooked at very high temperatures
– (e.g. by frying, broiling or barbecuing)
• If > one 1st -degree relative had the disease, and more
modestly if they developed it before the age of 50
Meat hanging inside a smokehouse in Switzerland.
12. • The genetic events found in ductal adenocarcinoma have been
well characterized, and complete exome sequencing has been
done for the common types of tumor
• 4 genes have each been found to be mutated in the majority of
• KRAS (in 95% of cases), CDKN2A (also in 95%), TP53 (75%),
and SMAD4 (55%).
• The last of these are especially associated with a poor
14. Familial pancreatic cancer( H3-AFP)
• Cystic fibrosis –30 fold increase in risk of PDAC (CFTR Gene mutation)
• Familial adenomatous polyposis - 4 fold increase. (APC Gene mutation )
• Predisposing conditions
– Hereditary pancreatitis (40% life time risk)
• PRSS1 gene mutation
– HNPCC (lynch syndrome)- 8 fold increase.
– Hereditary breast cancer assoc with BRCA2 mutation- 10 fold increase
• BRCA2 mutation is the MC germline mutation)
– Ataxia telengiectasia
– FAMMM( Familial atypical multiple mole & multiple melanoma)
syndrome- > 40% fold increase
• CDKN2A gene mutation.
– Peutz- Jeghers syndrome ( > 100 fold increase in risk of PDAC)
• Carries highest relative risk of PC.
• STK11 tumor suppressor gene
15. • Dysplastic nevus syndrome
• Atypical Mole Syndrome (AMS)
• Familial atypical multiple mole–
melanoma (FAMMM) syndrome
• It is a cutaneous condition described
in certain families, and characterized
by unusual nevi and multiple
17. • Patients with pancreatic cancer with DNA mismatch repair
mutation have a better prognosis.
• Kras mutation and HER2 /neu over expression are the earliest
changes to occur.
18. Pathogenesis of sporadic pancreatic cancer
• Most cases are sporadic
• 5–10% of pancreatic cancer cases have an inherited
• These cancers are thought to arise from several types of
precancerous lesions within the pancreas.
• But these lesions do not always progress to cancer
• Apart from pancreatic serous cystadenomas (SCNs), which
are almost always benign, three types of precancerous lesion
1. pancreatic intraepithelial neoplasia (PanIN)
2. intraductal papillary mucinous neoplasms (IPMNs)
3. pancreatic mucinous cystic neoplasms (MCNs)
19. 1.pancreatic intraepithelial neoplasia (PanIN)
• These are microscopic abnormalities in the pancreas, which
are often found in autopsies of people with no diagnosed
• These may progress from low to high grade and then to a
• Sequential pathway observed in the development of PDAC
from PanIN to invasive cancer.
• Number of tumor supressor & oncogenes are identified
• PDX1, KRAS2, CDKN2A/p16, P53 & DPC4 (SMAD4)
22. Classification cystic lesions in the
• Pancreatic cysts can be categorized into the following
• Common cystic neoplasms:
– SCN - Serous cystic neoplasm (Benign )
– IPMN - intraductal papillary mucinous neoplasm
– MCN - Mucinous cystic neoplasm
• Uncommon cystic neoplasms:
– SPEN (solid pseudopapillary epithelial neoplasm)
– Tumors with cystic degeneration:
25. Charecteristic SCN MCN IPMN
Gender F>>M 4:1 F>>>M 10:1 F=M
Age 60-70 (grandma) 50-60 (mother) 60-70
Location HEAD BODY TAIL HEAD
Appearance Multiple small cyst
Thick walled ,
contour, +/- solid
with dilaion of main
or branch ducts
No No Yes
Cytology Glycogen rich cells
with +ve PAS stain
Sheets & clusters
of collumnar mucin
Mucin stain -VE +VE +VE
Amylase LOW LOW HIGH
CEA LOW HIGH HIGH
26. Intraductal papillary mucinous neoplasms
• Macroscopic lesions, which occur in about 2% of all adults
• 25% risk of developing into invasive cancer.
• Also known as mucin secreting carcinoma
• MC in head and Uncinate process of the pancreas
• Types –
– Side branch- dilatation of PD side branch
– Main duct – abnl cystic dilatation of the main PD
– Mixed type – side branch IPMN which extent to main PD
• Even if removed surgically, there remains a considerably
increased risk of pancreatic cancer developing subsequently
28. Clinical features
• Lesion in the periampullary region, HOP, & uncinate process-
obstuctive jaundice (painless)
• Tumors from the body and tail of the pancreas- pain & LOW
• Pain typically arising in the epigastrium and radiating to the
back, when tumor spread beyond the pancreas peripancreatic
nerve plexuses are involved . Pain suggests unresectability in
• Ascitis- when peritoneal carcinomatosis or portal vein occlusion
29. • In case of pertoneal dissemination , perirectal tumor, involvement
may be palpable via DRE , referred to as Blumer`s shelf.
• Metastasis to liver and peritoneum most common
• A palpable distended GB in 1/3rd of patients with periampullary
PDAC ( courvoiser Law).
• With wide spread disease , a left supra-clavicular node
(Virchow`s node ) may be palpable.
• Perumbilical lymphadenopathy may be palapable (sister Mary
• 2/3rd (65%) pts present with diabetes in carcinoma pancreas
30. • Symptoms include unexplained episodes of pancreatitis,
• Elderly patients with A/c pancreatitis but with out H/o ETOH
or gallstones should be screened for a neoplasm
• Gastric Outlet Obstruction
• Clinical depression has been reported in association with
pancreatic cancer in some 10–20% of cases,
32. Other findings
• Trousseau`s syndrome : migratory thrombophlebitis
– ( blood clots form spontaneously in the portal blood vessels, the deep
veins of the extremities, or the superficial veins anywhere on the body,
may be associated with pancreatic cancer, and is found in about 10%
– CA lung, GI malignancies, Prostate cancer, Ovarian cancer,
– Mucins directly activate platelets via p selectin
– May explain why heparins more effective than warfarin in
adenocarcinoma related thrombosis
• Trousseau’s sign : carpopedal spasm in hypocalcemia
• Troisier’s sign : palpable left supraclavicular LN ( virchow’s
33. Periampullary carcinoma
• Periampullary carcinoma is term used for juxta-pancreatic
• They are three forms:-
Carcinoma of the ampulla
Carcinoma of the lower CBD
• Adenocarcinoma HOP 40-60%
• Adenocarcinoma of ampulla of Vater 10-20%
• Distal bile duct adenocarcinoma 10%
• Duodenal adenocarcinoma 5-10%
• Best prognosis:
– Duodenal adenocarcinoma > Adenocarcinoma of ampulla of Vater >
Distal bile duct adenocarcinoma > Adenocarcinoma Head>body >tail
34. • Most pancreatic cancers occur in the head of the pancreas
(75%), body (15%) and tail (10%).
• At the time of diagnosis a pancreatic head carcinoma is usually
a little larger than 3 cm.
• When tumors of the pancreatic body and tail are diagnosed,
they are usually much larger, because they present late with
• These tumors are usually irresectable.
36. Carbohydrate antigen , CA19-9
• CA 19-9 (most sensitive)
• It has a sensitivity of 80% and specificity of 73% in detecting
pancreatic adenocarcinoma, and is used for following known
cases rather than diagnosis.
• Individuals with blood Lewis antigen- negative status (10-
15%) do not develop elevation of the CA 19-9
• The degree of elevation post op is predictive of long term
• CA19-9 is elevated by biliary obstruction per se and is
elevated in other cancers (e.g., gastric, bladder…)
38. Ultrasound abdomen
• US is the first line imaging test for the evaluation of these
• sensitivity of 75% and a specificity of 75%.
• US can determine the level of obstruction in most cases
• The overall sensitivity and specificity for determining
resectability of all pancreatic carcinomas however is only
63% and 83% respectively.
• In patients with a pancreatic head tumor, typically dilatation of
the CBD & PD (double duct sign) is seen, which is s/o a mass
in the pancreatic head, even in the absence of a visible mass.
• Usg is less sensitive and will miss small tumors, but can
identify cancers that have spread to the liver and ascites
• MDCT is the ioc for evaluation, diagnosis, staging , & follow
up in CA pancreas.
• For suspected periampullary pathology, a 3 phase
(noncontrast, arterial, and portal venous ) CT scan with 3mm
slices and coronal & 3D reconstruction should be routine.
• If the cause of a distal bile duct obstruction is not revealed by
US , next diagnostic test is CT.
• As pancreatic carcinoma is a hypovascular tumor, it presents
as a hypodens mass on a CECT.
40. • The mass is usually ill-defined.
• In 10 - 15% the tumor is isodense and therefore may be difficult to
• Tumors smaller than 2 cm. may also be difficult to detect on CECT.
• In these cases indirect signs may be helpful such as the presence of
the double duct sign, atrophy of the pancreatic tail, or fullness of
the pancreatic head (loss of the lobular appearance of the
• CxR is sufficient to R/0 pulmonary mets if suspicious lesions noted,
• ERCP (or MRCP) is only the next step when there is a high
suspicion of bile duct stones.
• ERCP reserve for cases requiring therapeutic or palliative
• Double duct sign on ERCP is highly s/o pancreatic head cancer.
• Tissue diagnosis is not necessary prior to routine resection.
• A suspicious lesion by imaging should be treated with resection.
• Although ERCP has a high sensitivity for detecting pancreatic head
tumors, it is nowadays no longer indicated because the diagnosis can
usually be made with non-invasive tests.
• No role in tumor staging information
• For identifying lesions < 2cm that do not appear on CT scans
• These pancreatic head tumors can be missed even on a
technically excellent CT and therefore a 'negative' CT-scan in
a patient with a strong suspicion for pancreatic head cancer
requires additional imaging with endoscopic ultrasound.
• Endoscopic ultrasound has also been used for local tumor
45. • CT and MRI both have a higher sensitivity than ultrasound for the
detection of small lesion.
• CT scan & EUS are used both to confirm the diagnosis and to help
decide whether the tumor can be surgically removed (its
• MRCP is also very sensitive for detecting a periampullary mass, but
offers no significant additional staging information
• To differentiate autoimmune focal pancreatitis versus
adenocarcimnoma & also to identify unusual pathology (10%)
• PET has currently not proven its use in the differentiation as
tumor and inflammation may both show increased uptake
46. • A biopsy by fine needle aspiration, often guided by EUS may
• Histologic diagnosis is not usually required for removal of the
tumor by surgery to go ahead.
• Liver function tests can show a combination of results
indicative of bile duct obstruction (raised conjugated bilirubin,
γ-glutamyl transpeptidase and ALP )
• Focal pancreatitis, lymphoma and metastatic disease
• Most large surgical series show that, in about 5% of the patients,
who undergo resection for suspicion of pancreatic head cancer
only pancreatitis is eventually found in the resected specimen.
• The MC form of pancreatic cancer (adenocarcinoma) is typically
characterized by moderately to poorly differentiated glandular structures
on microscopic examination.
• There is typically considerable desmoplasia or formation of a dense
fibrous stroma or structural tissue consisting of a range of cell types
(including myofibroblasts, macrophages, lymphocytes and mast cells) and
deposited material (such as type I collagen and hyaluronic acid).
• This creates a tumor microenvironment that is short of blood vessels
• It is thought that this prevents many chemotherapy drugs from reaching
the tumor, as one factor making the cancer especially hard to treat
49. C shows ERCP imaging of a plastic stent through the ampulla of
Vater in a patient with a tumor in the head of the pancreas.
D (hematoxylin and eosin) shows microscopical adenocarcinoma
of the pancreas with abundant tumor stroma (black arrows).
E shows a peripancreatic lymph node involved with metastatic
adenocarcinoma (hematoxylin and eosin, high magnification).
• Pancreatic cancer is usually staged following a CT scan
• The most widely used cancer staging system is American Joint
Committee on Cancer (AJCC) together with the Union for
International Cancer Control(UICC).
• AJCC-UICC staging system
55. • To help decide treatment, the tumors are divided into 3 categories
– Borderline resectable
• Early stage ( stages I and II) - Surgical resection of the tumor can
normally be performed, if the patient is willing & to be sufficiently
• Stage III tumors - that are judged to be "borderline resectable"
(where surgery is technically feasible because the celiac axis and
SMA are still free)
• Stage 3 (T4) disease involving celiac artery or SMA or stage 4
(metastatic disease) are not candiadates for immediate surgery.
56. Resectable or Irresectable that's the question
• It is important to stage a pancreatic tumor correctly.
• Overstaging will lead to under treatment, if a laparotomy is not
performed in a patient with a potentially resectable tumor.
• Understaging will lead to an unnecessary laparotomy with all
the associated risks.
57. The pancreatic head is surrounded by the portal vein, SMA,
mesenteric root, duodenum, IVC and aorta
58. Not resectable- Liver metastases and distant lymph node metastases
should allways be proven by means of cytologic or histologic biopsy
before refraining from exploratory laparotomy.
62. Locally advanced adenocarcinomas
• Locally advanced adenocarcinomas have spread into
neighboring organs, which may be any of the following
– Duodenum >stomach> transverse colon> spleen> adrenal gland> or kidney.
• Back pain or highly elevated CA19-9
• Positive peritoneal washings has same prognosis as
metastatic disease so these patients considered metastatic
and not locally advanced
• 40% of newly diagnosed patients are locally advanced
• Locally advanced -prognosis (e.g. 1 year) ,metastatic disease
• Typical sites for metastatic spread (stage IV disease) are the
liver, peritoneal cavity and lungs, all of which occur in 50%
63. Non-resectable pancreatic head tumor obstructing the common bile duct and
Tumor surrounds the superior mesenteric vein at the junction with the splenic
vein. Paraaortic and celiac lymphnodes and a small liver metastasis.
• Staging laparoscopy reduces the frequency of non-therapeutic
laparotomy for pts with unsuspected metastatic or locally
advanced unrescectable disease identified at the time of
• Laparoscopy is much more sensitive than any other technique
for the detection of peritoneal implants and superficial liver
• For pts who appears resectable on imaging studies alone
turned out to be un-resectable in 30% of cases.
• Indicated in high risk occult disease
– large tumors>3cm
– CA 19-9 levels > 100 U/ml
– Equivocal findings of metastasis on CT
– Body or tail tumors
– Clinical indicators of wide spread d/s- sig LOW, malnutrition, pain
66. History/ surgery
• The earliest recognition of pancreatic cancer has been
attributed to the 18th-century Italian scientist Giovanni
• A genuine histopathologic diagnosis was eventually recorded
by the American clinician Jacob Mendes Da Costa
• By the start of the 20th century, cancer of the HOP had
become a well-established diagnosis
67. • The first reported partial pancreaticoduodenectomy - Italian
surgeon Alessandro Codivilla ( 1898)
• 1912 the German surgeon Walther Kausch was the first to
remove large parts of the duodenum and pancreas together (en
• American surgeon Allen Oldfather Whipple (1935) published
the results of a series of 3 operations at Columbia
Presbyterian Hospital in New York
• Two stage procedure- biliary decompression followed by
68. • The discovery in the late 1930s that vitamin K prevented
bleeding with jaundice, and the development of blood
transfusion as an everyday process, both improved post-
• 1970- median operating time 8.8hrs, mortality -25%
• 2000s- median operating time 5.5 hrs, mortality -1 %
• 1000 pancreaticoduodenectomies performed by a single
surgeon from Johns Hopkins Hospital Baltimore between
1969 -2003 (Trimble & colleagues)
• 2,050 operations at the Massachusetts General Hospital
1941 - 2011
• The only curative treatment option is surgical resection.
Tumor of HOP Pylorus preserving
procedure is preferred.
Tumor of body and tail Distal pancreatectomy
& en-bloc splenectomy
( Whipple’s procedure)
• It consist of complete removal of the pancreas and
hepatoduodenal ligament lymph nodes, the duodenum with a
short segment of the proximal jejunum and the distal half of
2/3rd of the stomach with the right half of the greater omentum
• Whipple’s procedure involves the resection of
– Distal stomach
– Head of pancrease
– Proximal jejunum
– Regional LN
73. Restoration of GI continuity requires
75. • Whipple is now reserved for situation in which
– the entire duodenum has removed (eg in FAP) or
– when the tumor encroaches on the first part of D or
– distal stomach & a PPPD would not achieve a clear
Middle or central or segmental pancreatectomy
Middle pancreatectomy is a safe, effective procedure for
treatment of benign & low grade malignant neoplasms of mid
•benign & low grade malignant neoplasms
( NET, serous cystadenoma, branch duct IPMNs)
•Location in neck or its contiguous position
•A distal pancreatic stump of at least 5 Cm in length
76. Middle or central or segmental pancreatectomy
• In experienced hands it is assoc with no mortality, even if rate
of clinical “ pancreatic fistula is about 20%.
• Middle pancreatectomy is avoided in pts affected by main duct
– Preserve pancreatic parenchyma
– Reduce the risk of exocine and endocrine insufficiency
– Consists of limited resection of the mid portion of the pancrease.
77. Morbidity following pancreaticoduodenectomy
COMPLICATIONS FREQUENCY %
DELAYED GASTRIC EMPTYING
PANCREAS FISTULA 12
WOUND INFECTION 7
CARDIAVC EVENTS 3
BILE LEAK 2
OVERALL REOPERATION 3
• MC cause of death following pacreaticoduodenectomy is cardiopulmonary
• Most important predictor of post-operative survival is R0 resection
• Most important margin in pacreaticoduodenectomy is retropertoneal or
78. Resectional surgery for pancreatic body and
• Most of body and tail tumors have already metastasized to
distant sites or extended locally to involve nodes, nerves, or
major vessels by the time of diagnosis
• Splenic vein involvement or occlusion is not a sign of
• Involvement of splenic and SMV confluence generally
• Resection involves a distal pancreatectomy either with or
without concomitant splenectomy
79. Palliative therapy for PC
Biliary obstruction 1)ERCP with metal stent
2)Roux-en – Y
GOO 1)Endoscopic stenting (prefered)
2)Double bypass (Roux-en-Y
Pain 1)NSAIDs or Opiates
2) Celiac nerve block
• Gemcitabine is current standard of care with metastatic PC.
• Folfirinox regimen- Nearly 3.6 month survival benefit
compared to Gemcitabine alone
(FOL – folinic acid (leucovorin), F – fluorouracil (5-FU),
IRIN – irinotecan (Camptosar), OX – oxaliplatin (Eloxatin))
• Folfox regimen :
(FOL– Folinic acid (leucovorin) F – Fluorouracil (5-FU) OX
– Oxaliplatin (Eloxatin)
– 5 yr survical after curative resection
(pacreaticoduodenectomy) approaches 15-20%
– Overall , 5 yr survival rate with PC is 5 %.
82. Meta-analysis in JCO, 2007
• Chemo is better than supportive care in terms of
• Gemcitabine better than 5FU
• Combinations of other drugs with gemcitabine
slightly superior to gem alone
• Tissue diagnosis- But in specific patients a tissue
diagnosis may be needed such as in patient entering a clinical
trial, prior to neoadjuvant chemoRx, and prior to chemoRx
in advanced tumors.
Sultana, A. et al. J Clin Oncol; 25:2607-2615 2007
Chemo-radiation vs chemotherapy alone
in locally advanced disease
Small old trial showed adding 5FU to radiation improves
survival compared to radiation alone but another trial
showed 5FU alone was as good as 5FU+radiation
Recent trial did not show benefit to adding radiation in
locally advanced disease
New chemotherapy regimens are more effective and have
higher response rates further putting into question role of
85. Metastatic tumor to pancreas
• MC site of primary : RCC> malignannt melanoma
• On autopsy MC site of primary : CA Lung
• For locally advanced and metastatic pancreatic
adenocarcinomas, which together represent over 80% of cases
• Numerous recent trials comparing chemotherapy regimes have
shown increased survival times, but not to > one year
• Overall 5 year survival for pancreatic cancer in the US has
– 2% in cases diagnosed in 1975–77
– 4% in 1987–89 diagnoses
– 6% in 2003–09.
– localized and small cancerous growth (<2 cm) -20%
Resectable disease (stage I &II) 15-20 months
Locally advance d/s (stageIII) 6-10 months
Metastatic disease (stage IV) 3- 6 months
88. Research directions
• Targeted therapies against the cancer cells (ruloxitinib with
capecitabine. (Jak activation is present in pancreatic cancer)
• Still others aim to affect the non-neoplastic stroma and
microenvironment of the tumor, which is known to influence
cell proliferation and metastasis
• A further approach involves the use of immunotherapy, such
as Oncolytic viruses
• Irreversible electroporation
89. Irreversible electroporation IRE or NTIRE
• A novel ablation technique
• IRE or NTIRE for non-thermal irreversible electroporation is a soft
tissue ablation technique using ultra short but strong electrical fields to
create permanent and hence lethal nanopores in the cell membrane, to
disrupt the cellular homeostasis.
• It is especially suitable for treatment of tumors that are in proximity to
peri-pancreatic vessels without risk of vascular trauma