PANCREATIC NEOPLASMS

Dr K Sreenath

Junior Resident, Dept of Surgery

RIMS Imphal

PANCREAS

Weighs between 75 and 125 g and measures 10 to

20 cm.

Lies in the retroperitoneum just anterior to the first

lumbar vertebrae

Divided into four portions, the head, neck, body

and tail.

PANCREAS ANATOMY

ARTERIAL SUPPLY

Multiple arcades in the head and body of the pancreas provide a rich blood supply.

The head of the pancreas cannot be resectedwithout devascularizingthe duodenum unless a rim of pancreas containing the pancreaticoduodenalarcade is preserved

VENOUS DRAINAGE

Follows a pattern

similar to the arterial

supply

Veins usually

superficial to the

arteries

LYMPHATIC DRAINAGE

The lymphatic drainage from the pancreas is diffuse and widespread, which explains the high incidence of lymph node metastases and local recurrence of pancreatic cancer.

The pancreatic lymphaticsalso communicate with lymph nodes in the transverse mesocolonand mesentery of the proximal jejunum.

Tumors in the body and tail of the pancreas are often unresectable because they metastasize to these lymph nodes

INNERVATION

The pancreas has a rich supply of afferent sensory fibers that travel superiorly to the celiac ganglia.

Interruption of

these somatic fibers with a celiac plexus block can interfere with transmission of pancreatic pain

TYPES OF PANCREATIC NEOPLASMS

Neoplasms of exocrine pancreas

Cystic neoplasms account for <1% of

pancreatic cancers

Ductal adenocarcinoma >90% of pancreatic

cancers

Neoplasms of endocrine pancreas

Neuroendocrine tumors or islet-cell tumors,

rare

CARCINOMA EXOCRINE PANCREAS

MC – Ductal adenocarcinoma

Ninth most common cancer diagnosis

Fourth in cancer deaths

Men> women (1.3 : 1)

African Americans have a slightly higher risk

Mean age at diagnosis is 72 years

Incidence lowest in Middle East and in India

RISK FACTORS-ENVIRONMENTAL

Smoking

C/C Pancreatitis

Occuopational exposure

Diabetes

Obesity

Diet ( Rich in protein and fat)

Infectious - H pylori or HBV ?

Genetic

Alcohol , coffee and Radiation ..No Risk

(Maingot’s 12th edn p. 1188)

RISK FACTORS-HEREDITARY

PATHOGENESIS

Most cases are sporadic.

Sequential pathway has been observed in the development of PDAC from pancreatic intraepithelial neoplasia (PanIN) to invasive cancer.

Genes identified- PDX1, KRAS2, CDKN2A/p16, P53, and DPC4 (SMAD4).

KRAS2 oncogene is activated (by point mutation ) 95% of pancreatic cancers

Earliest event in tumorigenesis.

PanIN :

Progressive abnormality of the ductal epithelium from

columnar metaplasia (PanIN-1A) through carcinoma in

situ (PanIN-3).

PanIN-1A : Presence of columnar, mucin-producing ductal

epithelium

PanIN-1B : The development of papillary architecture

PanIN-2 : Evidence of nuclear atypia

PanIN-3 (carcinoma in situ): marked cytologic atypia,

complete loss of polarity

MOLECULAR GENETIC PROGRESSION FROM PANIN TO

INVASIVE DUCTAL ADENOCARCINOMA.

PERIAMPULLARY CARCINOMA

Adenocarcinomas of the

Head of the pancreas

Ampulla of Vater ,

Distal bile duct (cholangiocarcinoma),

Duodenum .

Less commonly, acinar cell carcinomas or

pancreatic endocrine neoplasms occur in the

periampullary region of the pancreas

CLINICAL PRESENTATION

CARCINOMA BODY AND TAIL

Late presentation

Pain and weight loss are more common

Rare

Poor prognosis

SIGNS

A palpable distended gallbladder (Courvoisier’s law)

Left supraclavicular node (Virchow’s node & Troisier’ssign )

Periumbilical lymphadenopathy may be palpable (Sister Mary Joseph’s node).

Peritoneal dissemination and perirectal tumor involvement may be palpable via digital rectal examination (Blumer’s shelf)

Migratory suprficial thrombophlebitis (Trousseau ‘s sign)

LABORATORY EVALUATION

Hepatic function evaluation

Coagulation profile

Nutritional assessment.

Tumor markers : CEA, CA19-9

CA19-9

Most sensitive most reliable tumor marker

for pretreatment evaluation and post-

treatment surveillance

IMAGING STUDIES

Ultrasound abdomen

Initial ivestigation

Multiphase Multidetector CT

- The imaging study of choice

- Three-phase (noncontrast, arterial,

and portal venous) CT scan with 3-

mm slices and coronal and 3 D

reconstruction

- Extension to SMA, Celiac axis, SMV-PV complex

and contiguous structures can be determined

- Metastasis can be asessed

- Resectability can be predicted

US is often the initial test in symptomatic patients.

US is used for diagnosis rather than staging, although liver metastasis and

ascites may be seen.

Ultrasound

normal anatomy

CT Findings

Axial CT image shows stage

T1 pancreatic ductal

adenocarcinoma

Drawing shows T1 tumor, which is

defined as being equal to or smaller

than 2 cm in maximum diameter and

confined to pancreas, and T2 tumor,

larger than 2 cm and confined to

pancreas

CT Findings

Drawing shows T3 tumor, defined as

tumor that may extend beyond

pancreas but without involvement of

celiac axis or superior mesenteric

artery.

Contrast-enhanced axial CT image shows T3 tumor that

has involved common bile duct, requiring a stent, and that

extends medially beyond confines of pancreatic head.

Tumor is separated from superior mesenteric vein (long

arrow) and superior mesenteric artery (short arrow) by fat

plane (type A relationship). Note that tumor involves

duodenum (arrowhead).

CT Findings

Drawing shows T4 tumor, defined as

primary tumor involving either

superior mesenteric artery or celiac

axis.

Contrast-enhanced axial CT image shows

pancreatic tumor (white arrows) engulfing

celiac axis. Short black arrow = splenic

artery, long black arrow = common

hepatic artery.

Endoscopic US

To provide tissue diagnosis of suspected tumors through FNA prior to

initiating systemic therapy.

Beneficial for identifying small tumors smaller than 2 cm

A 2.5cm round, hypoechoic

tumor is identified in the the

region of the genu. The

superior mesenteric vein can

be seen separate from the

tumor.

Invasion of the dilated CBD

by a large irregular

hypoechoic tumor located in

the head of pancreas.

A large hypoechoic tumor is seen to

invade the portal vein (arrow), with

loss of tumor-vessel interface and

tumor extension into vessel lumen.

The dilated CBD contains echogenic

sludge.

MRI Findings

The role of MRI in pancreatic cancer has been less well studied than the role of

CT scanning. It does not appear to be superior to spiral CT scanning.

The ability of MRI to demonstrate pancreatic adenocarcinoma largely depends on

the demonstration of deformity of the gland, as reflected in its size, shape, contour,

and signal intensity characteristics.

Thin-section helical CT image obtained during

pancreatic phase reveals large pancreatic

tumor with tumor surrounding celiac trunk and

hepatic artery.

Extent of vascular encasement is better

depicted by CT scan than by MR images.

T1 contT1

MRI Findings

Transverse T1-weighted fat-

suppressed image shows

verified adenocarcinoma of

the pancreatic head

Adenocarcinoma was visible

as a low-signal-intensity

tumor.

The normal pancreas is of

low signal intensity on T1-

weighted images and of

intermediate signal on T2-

weighted images, with a

variable amount of fat in the

gland parenchyma.

MRCP

Assessment of luminal pancreatobiliary anatomy

Usefull for cystic lesions of the pancreas

ERCP

- To perform a biopsy and palliate

jaundice (biliary stenting)

Signs

Abrupt block

PD encasement

Dubble duct sign

Scrambled egg appearance

ERCP has a sensitivity of 95% and a

specificity of 85% for pancreatic

malignancy.

Most pancreatic carcinomas arise from

the ductal epithelium and produce

complete or partial ductal obstruction.

ERCP image

shows dilated

biliary tree and

obstruction of

common bile

duct associated

with tumor in

pancreatic

head.

Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP image shows

slight narrowing of

pancreatic duct and

ductal dilatation.

Sphincterotomy was

performed, and

pancreatic stent was

placed.

Contrast-enhanced CT

scan fails to depict

tumor (arrow) around

stent in dilated common

bile duct.

Unenhanced T1-weighted MR

image shows inhomogeneity of

pancreatic head, but does not

show tumor.

Compared with other modalities, MRI appears to be more valuable for staging the

extent and spread of pancreatic carcinoma than for tumor detection of lesions

smaller than 2 cm.

Magnetic resonance cholangiopancreatography (MRCP)

MRCP is as sensitive as ERCP and may prevent inappropriate explorations of

the pancreatic and bile ducts in patients with suspected pancreatic carcinoma in

whom interventional endoscopic therapy is unlikely

Coronal image from MRCP

shows double-duct sign

caused by obstruction by

tumor.

Dilated common bile duct and

dilated pancreatic duct are

seen proximal to abrupt

cutoff.

Magnetic resonance cholangiopancreatography (MRCP)

MR pancreatogram reveals a dilated

pancreatic duct proximal to the

obstructing pancreatic head mass.

ERCP helps confirm the dilatation of the

pancreatic duct in the body and the distal

stricture.

MRI Findings

Coronal oblique MRCP demonstrates

pancreatic duct obstruction in the head

with proximal dilatation of both pancreatic

duct (PD) and common bile duct (CBD),

which is referred to as the double duct

sign.

Coronal MR angiogram in the venous phase

shows vascular infiltration of the portal vein

and venous confluens. Note the consecutive

mesenteric collateral formation.

>The medial margin of the

descending duodenum may be pulled

medially at the level of the ampulla,

forming a reversed-3 appearance.

This is known as Frostberg 3 sign.

>Rose thorn appearance

Duodenal invasion at

the level of papilla major

demonstrated by upper

GI endoscopy

Upper GI barium studies may

reveal an extrinsic impression of

the mass on the posteroinferior

aspect of the antrum of the

stomach, widened C loop of

duodenum

This is known as antral pad

sign”.

Percutaneous transhepatic cholangiogram(PTC)

>Percutaneous

transhepatic

cholangiogram showing a

catheter in a dilated

common bile duct with an

abrupt, irregular

stricture at the lower

end, indicative of a

pancreatic cancer

>Not used routinely due

to other less invasive

imaging modalities

STAGING

Following CT imaging, patients are classified into resectable,

borderline resectable, or unresectable.

Resectable tumors -

Localized to the pancreas, with no evidence of SMV or portal

vein involvement and a preserved fat plane

Borderline resectable

(1) severe unilateral or bilateral SMV-portal impingement;

(2) less than 180-degree tumor abutment on the SMA

(3) abutment or encasement of hepatic artery, if reconstructible

(4) SMV occlusion, if of a short segment, and reconstructible.

Unresectable tumors -

Those that exhibit metastasis, including lymph node metastasis

outside the field of resection, ascites, or vascular involvement

STAGING LAPROSCOPY

Indications

Large tumors (>3 cm)

Significantly elevated CA19-9 level (>100 U/mL)

Uncertain findings on CT

Body or tail tumors

PREOPERATIVE PREPARATION

Correction of anemia

Replenishment of glycogen store

Correction of dehydration

Injection of vitamin K

Adequate IV fluids and mannitol to ensure

adequate diuresis

Broad spctrum antibiotics 1-2 days prior

Enteral or parenteral nutrition

Pulmonary physiotherapy

Preoperative biliary drainage – contraversial

TREATMENTHead of the pancreas

> Pancreaticoduodenectomy is the

procedure of choice.

(Either Wipple’s or Traverso and Longmire)

> Laparoscopic Pancreaticoduodenectomy

Body and Tail of the Pancreas

Distal pancreatectomy and en

bloc splenectomy

PANCREATICODUODENECTOMY – 6 STEPS

1. A Cattell-Braasch maneuver

2. Extended Kocher maneuver

3. Portal dissection

4. Transect stomech

5. Transect jejunum

6. Transect pancreas and

complete retroperitoneal

dissection

PANCREATICODUODENECTOMY-

RECONSTRUCTIONS

1. End to side PJ

2. End to side HJ

3. End to side GJ

( antecolic)

STRUCTURES REMOVED

Distal stomach

Gall bladder

CBD

Head of Pancreas

Duodenum

Proximal jejunum

Regional lymphatics

ADJUVANT THERAPY

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 consisting of a Roux-en-Y

hepaticojejunostomy and gastrojejunostomy

Pain Relief

NSAIDS or long acting opioids

Celiac nerve block

Neurolysis

RECENT ADVANCES

Immunotherapy

Allogenic tumor cell vaccine under phase 2 trial

Angiogenesis inhibitors

Becacizumab (anti VEGF) with gemcitabine under

phase 3 trial

K ras inhibitors

Tipifarnib ( farnesyl transferase inhibitor)- studied and

showed no improvement in outcome

EGFR inhibitors

EKB 569 and erlotinib

Erlotinib approved for treatment of unresectable

cancer( study by NCI of Canada)

CYSTIC NEOPLASMS OF THE PANCREAS

CYSTIC NEOPLASMS OF THE PANCREAS

Second most common exocrine pancreatic

neoplasm next to adenocarcinoma.

Types

Mucinous

Serous

IPMN

MUCINOUS CYSTIC NEOPLASM

Most common cystic neoplasms of the

pancreas.

Young women, Men are rarely affected.

Fifth decade.

Typically found in the body and tail of the

pancreas

Contain mucin-producing epithelium

Presence of mucin-rich cells and ovarian-like stroma

CT scan –

solitary , fine septations, surrounded by a rim of calcification

Predictors of malignancy

Eggshell calcification,

larger tumor size

mural nodule on cross-sectional imaging

EUS and cyst fluid analyses demonstrate

mucin-rich aspirate and

high CEA levels (>192 ng/mL)

low levels of amylase

Standard treatment - Pancreatic resection

SEROUS CYSTIC NEOPLASM

Predilection for the head of the pancreas

Vague abdominal pain and less frequently with weight

loss and obstructive jaundice

Large , wellcircumscribed masses.

Microscopy - multiloculated, glycogen-rich small cysts.

CT Scan-

Central calcification, with radiating septa giving the

sunburst appearance (10-20%)

Large (>4 cm) or rapidly growing, symptomatic lesion

Treatment is Resection

Small (<4 cm) , asyptomatic can be observed.

INTRADUCTAL PAPILLARY MUCINOUS

NEOPLASM

First described by Ohashi

Several names—

Mucin secreting carcinoma

Villous adenoma of the duct of Wirsung

Diffuse intraductal papillary adenocarcinoma

Intraductal cystadenoma

Mucinous duct ectasia, and

Intraductal papillary mucinous tumor.

Sixth to seventh decade of life.

Commonly in head region.

Wide spectrum

ranging from benign adenoma, borderline, carcinoma in

situ, and invasive adenocarcinoma.

Types-

Side branch or branch duct IPMN,

Main duct IPMNs,

Mixed -type IPMNs

SIDE BRANCH IPMN

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

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%

MAIN DUCT IPMN

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 harboring invasive pancreatic cancer at the

time of presentation.

Treatment- Surgical resection

(Risk of malignant transforamtion)

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

CT scans –

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; log scale)

MIXED-TYPE IPMN

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

NEOPLASMS OF ENDOCRINE PANCREAS

Paul Langerhans medical student, in 1869

pale staining cells within the pancreas

Alpha (A) – Glucagon

Beta (B) – Insulin and amylin

Delta (D) – Somatostatin and

vasoactive intestinal

peptide (VIP)

F cells – Pancreatic

polypeptide (PP)

Gastrin-producing cells are normally present in the fetal pancreas only.

ISLET CELL TUMORS

Very rare

Most are benign and

nonfunctional.

The incidence of malignancy varies from 10% in

insulinomas to almost 100% in glucagonomas.

Insulinomas, glucagonomas, and VIPomas arise

from the pancreas, whereas most gastrinomas

occur in the duodenum.

MOLECULAR GENETICS

Distinct from that of pancreatic adenocarcinoma.

Transcriptional silencing is believed to play a

role in islet cell tumorigenesis.

Loss of heterozygosity (LOH) 11q is common in

functional pancreatic endocrine tumors

LOH 6q is associated with the development of

nonfunctional tumors.

INSULINOMA

Most common functioning tumor

Equal distribution in the head, body, and tail.

97% are located in the pancreas, remaining 3% are located in the duodenum, splenic hilum, or gastrocolicligament

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.

72 hour fast 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

because of their rich

vascular supply

GASTRINOMA

Second most common functional pancreatic endocrine tumor

Cell of origin is not clear, because the normal adult pancreas has no gastrin-producing cells.

More common in men

Produce Zollinger-Ellison syndrome (ZES)

Hypergastrinemia , subsequent severe peptic ulceration, severe diarrhea.

Abdominal pain (75%)

Diarrhea releived by nasogastric

aspiration

Symptoms of GERD

Gastrinoma triangle (90%)

The cystic duct CBD junction

The jn between the second and

third portions of the duodenum

Junction between the neck and

body of the pancreas

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

VIPOMAS

Release high levels of VIP

Verner-Morrison syndrome

Also known as WDHA syndrome (watery diarrhea,

hypokalemia, achlorhydria) or pancreatic cholera.

Solitory , larger than 3 cm ; 75% body and tail

Hypokalemia, hypomagnesemia, hypo or achlorhydria,

hypercalcemia.

GLUCAGONOMAS

Very rare

Tend to be larger, averaging 5 to 10 cm in size

Most are malignant

Almost always arise in the pancreas and 65% to 75% are found in the body or tail.

A fasting glucagon level higher than 50 pmol/L is considered diagnostic.

The glucagonoma syndrome:

4Ds: diabetes, dermatitis, deep vein thrombosis, and depression

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

NONFUNCTIONAL NEUROENDOCRINE TUMORS

Defined as a pancreatic tumor of endocrine origin,

with no definable hormonal syndrome.

Late in seeking help hence most tumors are

malignant and metastasized at the time of

presentation

Identified by positive immunostaining for

chromogranin A or synaptophysin.

LOCALIZATION

Cross -sectional imaging with CT or MRI

first step in localization.

sensitivity is 71% to 82% and is directly related to

the size of the tumor.

vascular blush in the arterial phase is critical

lesions smaller than 1cm cannot be identified.

Endoscopic ultrasound (EUS)

Overall sensitivity of 93%

Greater sensitivity when compared with CT and MRI for

detecting tumors < 3 cm

Allows for fine-needle aspiration (FNA) of tumors

Somatostatin receptor scintigraphy (SRS)

Not useful for insulinoma

The sensitivity for SRS is over 80% for all pancreatic

endocrine tumors excluding insulinomas

It has an overall sensitivity of 80% to 100% and

specificity higher than 90% for gastrinomas.

SRS may not show the exact location of a tumor

indicates its vicinity within a few centimeters

Angiographic techniques and portal venous

sampling (sensitivity higher than 90%)

Blind exploration with intraoperative ultrasound

TREATMENT

The treatment of endocrine tumors is surgical.

(pancreatic head resection, distal pancreatic resection, or

enucleation.)

Performed by open or laparoscopic approaches

Insulinoma – Enucleation

Metastatic _ Streptozotocin, with or without 5-fluorouracil

Gastrinoma

Small well encapsulated _ Enucleation

Large unencapsulated _ Require segmental resection,

including distal pancreatectomy or

pancreaticoduodenectomy.

Radiation therapy and chemotherapy are ineffective.

VIPomas, glucagonomas, somatostatinomas, and

nonfunctional pancreatic endocrine tumors-

Resection is the treatment of choice for and

remains the only curative option.

Dacarbazine is uniquely effective against glucagonoma.

THANK YOU