Benign and Malignant Tumors of The Pancreas

MEDCAL UNIVERSITY OF SOFIA

Nur UYANIK

ANATOMY

The pancreas is an abdominal glandular organ, with a digestive (exocrine) and hormonal (endocrine) function. The normal pancreas is about 15 cm in length, approximately 120 g, and is located in the retroperitoneum. It is a retroperitoneal structure (lies behind the peritoneal cavity), located deep within the upper abdomen in the epigastrium and left hypochodrium regions.

Stomach lies anteriorly and superiorly.

Duodenum situated anteriorly and medially, curving around the head of the pancreas.

Spleen located posteriorly and laterally. It is connected by ligaments to the tail of the pancreas.

Vasculature the aorta and inferior vena cava pass posteriorly to the head of the pancreas.

ANATOMIC RELATIONSHIPS OF THE PANCREAS

The pancreas is typically divided into five parts;Head: This is the widest part of the pancreas. It lies within the C-shaped curve created by the duodenum, and is connected to it by connective tissue.

Uncinate process: This is a projection arising from the lower part of the head and extending medially to lie beneath the body of the pancreas. It lies posterior to the superior mesenteric vessels.

Neck: Located between the head and the body of the pancreas. It overlies the superior mesenteric vessels which form a groove in its posterior aspect.

Body: The body is centrally located, crossing the midline of the human body to lie behind the stomach and to the left of the superior mesenteric vessels.

Tail: The left end of the pancreas that lies within close proximity to the hilum of the spleen. It is contained within the splenorenal ligament with the splenic vessels. This is the only part of the pancreas that is intraperitoneal.

Duct System

The exocrine compartment is classified as a serous gland. It is composed of approximately a million berry-like clusters of cells called acini, connected by short intercalated ducts.

Intercalated duct cells beginning within acini are called centroacinar cells. The intercalated ducts drain into a network of intralobular collecting ducts, which in turn drain into the main pancreatic duct.

The pancreatic duct runs the length of the pancreas and unites with the common bile duct, forming the hepatopancreatic ampulla of Vater. This structure opens into the duodenum. Secretions into the duodenum are controlled by a muscular valve the sphincter of Oddi. It surrounds the ampulla of Vater, acting as a valve.

Vasculature

The pancreas is supplied by the pancreatic branches of the splenic artery. The head is additionally supplied by the superior and inferior pancreaticoduodenal arteries which are branches of the gastroduodenal and superior mesenteric arteries, respectively.

Venous drainage of the head of the pancreas is into the superior mesenteric branches of the hepatic portal vein. The pancreatic veins draining the rest of the pancreas do so into the splenic vein.

This classification is used to denote the location of metastatic spread of pancreatic neoplasms or for other detailed studies.

PHSYOLOGY OF THE PANCREAS

The endocrine islets of Langerhans which secrete insulin, glucagone and somatostatin.

Acinar gland tissues which produce pancreatic juice ( the main source of digestive enzymes). The cells lining the acini are serous cells containing zymogen granules.

Pancreatic Secretion

Pancreatic juice is secreted in response to the presence of chyme in the upper portions of the small intestine.

The major functions of pancreatic secretion:- To neutralize the acids in the chyme .-To produce enzymes involved in the digestion of dietary carbohydrate, fat, and protein.

Pancreatic Secretion -The volume:- 1.2-1.5 L/day. -The osmolarity of pancreatic fluid is equal to that of plasma (isotonic). - pH= 8 alkaline. -The electrolytes They are produced from the epithelial cells of the ductules and ducts and include cations Na +, K +, Ca ++ and anions HCO3 - and Cl

ENDOCRNE PANCREAS

(B) cells: Constitute 70% of islet cells. Concentrated in islet center. Function: secrete insulin which blood sugar.

(A) cells: Constitute 15-20%. Concentrated in islet periphery. Granules are much more numerous, more tightly packed, smaller, and denser than those of cells. Function: secrete glucagon which blood sugar.

(D) cells: (D) cells: Constitute 5-10% of islet cells. Function: secrete somatostatin which release of hormones from endocrine pancreas and enzymes from exocrine pancreas.

G cells: Constitute 1% of islet cells. Function: secrete gastrin which production of HCl by parietal cells of stomach.

PP cells: Constitute 1% of islet cells. Function: secrete pancreatic polypeptide which exocrine secretions of pancreas.

CANCERS OF EXOCRNE PANCREAS

BENIGN Serous cystadenoma

Mucinous cystadenoma

Intraductal papillary mucinous adenoma

Mature cystic teratoma

MALIGNDuctal adenocarsinoma

Serous-mucinous cystadenocarcinoma

Intraductal mucinous papillary tumor

BORDERLINEMucinous cystic tumor

Intraductal papillary mucinous tumor

Solid pseudopapillary tumor

EPIDEMIOLOGY

Age

Obesity

Family history

Smoking

Chronic pancreatic disease

Cystic tumors of the pancreas

Cystic tumors of the pancreas derive their name from the presence of fluid in the tumor.1.Serous cystadenoma 2.Mucinous cystadenoma3.Intraductal papllary mucinous adenoma

1.Serous cystadenoma : Generally bengn , no malgnant potential.

Can be found anywhere in the pancreas but frequently in the HEAD of the pancreas.

Also known as a microcystic adenoma and is a second most common cystic tumor of the pancreas.

These tumors have a honeycombed appearance.

Diagnosis is made based on a characteristic CT scan for this tumor.

Mean age 66, 70% women, associated with von Hippel Lindau syndrome

Symptoms: local discomfort/pain, obstruction if in pancreatic head; may cause diabetes if tumor destroys enough islets

Excision is almost always curative

2.Mucinous cystadenoma.. Patient: 9:1, F:MMucinous cystadenomas are the most frequent cystic tumors of the pancreas . While these tumors are usually benign, if left untreated will probably evolve to a malignant tumor.

80% of mucinous cystic tumors occur in females and the majority of the tumors occur in the younger female.

Abdominal pain or mass

< 20% associated with invasive carcinoma

Metastases usually restricted to abdominal cavity; metastases to ovary may simulate primary ovarian tumors

Can also occur in the liver

The surgical procedure depends on the location of the tumor. The vast majority of these tumors are precancerous. Because it is a precancerous tumor ,pancreatic head resection preserving the duodenum and the bile duct is offered.

Generally located in the body and the tail of the pancreas.

Intraductal papllary mucinous adenoma (IPMN) Patient: M=W Epithelial neoplasm of mucin-producing cells, arising in the main pancreatic duct or its branches.

has replaced such terms as mucin-producing tumor and mucinous ductal ectasia.

Mostly seen in HEAD of the pancreas.

High risk for malgn transformation.

More common in men age 60+ at head of pancreas

Signs and symptoms include epigastric pain, weight loss, jaundice, diabetes, pancreatitis

Pancreatic pseudocysts

Pancreatic pseudocysts most often develop after an episode of acute pancreatitis.

The cyst happens when the ducts (tubes) in the pancreas are damaged and fluid with enzymes cannot drain.

Bloating of the abdomen

Constant pain or deep ache in the abdomen, which may also be felt in the back

Difficulty eating and digesting food

Does not include epithelial cell in aspirated fluid !!!!

Possible treatments include:Drainage through the skin using a needle, most often guided by a CT scan

Endoscopic-assisted drainage using an endoscope (a tube containing a camera and a light that is passed down into the stomach)

Surgical drainage of the pseudocyst, which involves making a connection between the cyst and the stomach or small intestine. This may be done using a laparoscope.

ADENOCARCINOMA

The most common ( 85% ) type of all cancerous tumors of the pancreas are adenocarcinomas.

HEAD ---> 60-70 %

BODY ---> 15-20 %

TAIL ---> 5-10 %

1955-2011

>Pancreatic Adenocarcinoma Prognosis 20 % survival at 1 yr

Pancreatic Adenocarcinoma Risk Factors

Smoking (biggest)

> 50 yrs old

Diets high in fat

Obesity

Hereditary Pancreatitis

MEN

Dabet

...

K-ras oncogen

HER-2 / neu oncogen activationand ALSO :

P16

P53

BRCA2

DPC4 tumor supressor gene mutations are involved.

Pancreas head Adenocarcinoma Clinical Presentation (70 % of lesions)-Jaundice -Steatorrhea-Constant pain: radiates to the back-Courvoisier's signpancreas tail Adenocarcinoma Clinical Presentation -Diagnosed later than head lesions-Weight loss-Constant pain: radiates to the back

Clinical findings

Generally ;;;;Late onset of clinical presentation

Epigastric pain

Head --> jaundice

Body and tail --> x

Weight loss is most common symptom.

Trousseau sign (thrombophlebitis migrans)

Courvoiser terrier

Trousseau sign of malignancy

Due to release of PAF (platelet aggregating factor ) from the tumor or necrotic tissue around the tumor .

jaundice

Courvoisiers sign (or law) describes an enlarged, palpable gallbladder in patients with obstructive jaundice caused by tumors of the biliary tree or by pancreatic head tumors. The gall bladder will be dilated, with a thin wall; it is not tender to the touch.

DIAGNOSTIC

Laboratory: higher bilirubin, tumormarker CA 199 (but is not specific, can be found in patients with colon cancer or biliary obstruction);

USG: in clasical ultrasonography need not to be found small tumors of pancreas (or even pancreas);

EUSG: endoscopic sonography is better methode for finding of pathologies in pancreas than clasical abdominal USG;

ERCP (endoscopic retrograde cholangio-pancreatography) is the best methode for therapeutic intervention of biliary obstruction (stent)

CT: computer tomography is always neccesary in staging of pancreatic cancer, results of CT will decide about the therapy.

TREATMENT

Curative therapy1..Surgery

Whipples operation (partial pancreatico-duodenectomy) pancreatic head tumors

total pancreatico-duodenectomy (with gastro-jejunoanastomosis), then is neccesary pancreatic enzymes and hormones substitution

resection of the tail of pancreas (just only in pancreatic tail tumors).

Chemotherapy

There is no chemotherapy bringing better resultes than 68 months survival time. At this time is used:

5FU 5 fluoruracil;

gemcitabine.

Palliative Therapy Palliative therapy is based on patients symptoms:

therapy of pain analgetics, epidural analgesia or coeliac ganglion destruction;

therapy of biliary obstruction metalic stents via ERCP or hepatico-jejuno anastomosis (surgery);

therapy of gastrointestinal obstruction (especially duodenal obstuction by pancreatic head tumor) gastro-jejuno anastomosis.

Tumor of ampulla of vater

Production of local carcinogens through the combined interactions of the components of bile, pancreatic juice, and duodenal contents. Both benign and malignant tumors of the ampulla of Vater occur. The benign tumors include adenomas, gastrointestinal stromal tumors (GISTs), lipomas, and neuroendocrine tumors. ADENOMA AND ADENOCARCINOMA Most common malignant tumor of the ampulla of Vater .

Weight loss occurs in 75% of patients Abdominal pain in 50% Occult gastrointestinal bleeding is common, in one third of patients Nonspecific symptoms such as anorexia, dyspepsia, and malaise Rarely, with pancreatitis secondary to pancreatic duct obstruction With features of sphincter of Oddi dysfunction .

Physical examination include conjunctival or cutaneous icterus and, less commonly, hepatomegaly, a distended gall-bladder.

Diagnosis The earliest and most common laboratory abnormality is an increase in the serum alkaline phosphatase level Followed by hyperbilirubinemia as the tumor obstructs the bile duct. No tumor markers have been identified that are either sensitive or specific The first imaging modality should be ultrasonography or CT to determine the level of biliary obstruction. Dual-contrast helical CT is the most informative . ERCP is often the next procedure for patients with a suspected ampullary malignancy .

Staging Primary Tumor (T Stage) T1 Tumor limited to ampulla of Vater

T2 Tumor invades duodenal wall

T3 Tumor invades 2 cm into pancreas

T4 Tumor invades >2 cm into pancreas and/or adjacent organs Regional Lymph Nodes (N Stage)

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

Distant Metastasis (M Stage) M0 No distant metastasis

M1 Distant metastasis TNM Stage Grouping

Stage I T1 N0 M0

Stage II T2-3 N0 M0

Stage III T1-3 N1 M0

Stage IVA T4 N0-1 M0

Stage IVB T1-4 N0-1 M1

local resection of ampullary tumors is reserved for patients with a benign adenoma or ampullary neuroendocrine tumor and for highly selected patients with ampullary adenocarcinoma The options for local treatment are endoscopic snare removal, endoscopic ablation, and surgical ampullectomy.

Endescopic ampullectomy

Endocrine tumors of pancreas

Neuroendocrine tumors (NETs) are rare tumors (incidence rate, 5 cases per 1 million person-years) that arise from endocrine cells within or near the pancreas and account for less than 5% of all pancreatic tumors.

sporadically or as part of inherited genetic syndromes such as multiple endocrine neoplasia type 1, neurofibromatosis...

Most primary NETs arise within the gastrinoma triangle, composed of the joining of the cystic and common hepatic ducts, second and third portions of the duodenum, and border of the body and tail of the pancreas.

A special epidemiology.. MEN

The term multiple endocrine neoplasia is used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.

APUD cells : unrelated endocrine cells. common function of secreting a low molecular weight polypeptide hormone.

APUD cells in pancreas :insulin , gastrin, somatostatin, pancreatic polypeptide.

gastric APUD cells :gastrin, glucagon , substance P .

Intestinal APUD cells : motilin , substance C , enteroglucagon, secretin , somatostatin

INSULINOMA

Most common

90% -- bengn

10% -- malgnant

10% --part of MEN 1

Increased insulin and C peptide levels

Cerebral glucose dercrease leads to symptoms such as : convulsion , loss of memory , behavioral changes...

Ct endoscopic ultrasonography

TREATMENT : Distal pancreatectomy , enucleation (refers to the surgical removal of a mass without cutting into or dissecting it )

Blood glucose:
< 50mg /dl

GASTRNOMA

Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.

A gastrinoma is a gastrin-secreting tumor .More than 80% of gastrinomas arise within the triangle ( passaro triangle ).

25% -- MEN 1.

OCTEREOTDE SCINTGRAPHY ! Octreotide is a synthetic analogue of somatostatin .Tumors with high expression of somatostatin receptors ARE DETECTED.

PATOPHYSOLOGY

Prognosis

Patients with hepatic metastases may have a remaining life span of less than 1 year; the 5-year survival rate is 20-30%.

In patients with localized disease or metastasis to local lymph nodes without liver metastasis, the 5-year survival rate may be 90%.

Surgical resection of localized disease leads to a complete cure without any recurrence in 20-25% of patients with gastrinomas.

Treatment

Symptomatic treatmentProton pump inhibitor; octreotide

Enucleation: Many small gastrinomas in the pancreas may be treated by enucleation alone. This is a procedure of choice for patients that have small tumors (less than 1cm) where the tumor is located on the surface of the pancreas.

Resection of the pancreas: in patients with large tumors a distal pancreatectomy or a Whipple operation may be indicated depending on where the tumor is located in the pancreas.

Duodenal exploration: Gastrinomas often occur in the wall of the duodenum (first part of the intestine) and therefore opening duodenum and carefully feeling it to remove any tumors in this area is important.

Lymph nodes: In some patients the tumor may be located in the lymph glands outside the pancreas therefore careful palpation and removal of these glands is important at the time of surgery

Other neuroendocrine tumors such as glucagonoma, VIPoma and somastatinoma are extremely uncommon tumors. These tumors are malignant in the vast majority of patients and may present as large tumors at the time of diagnosis. Up to 70% of patients have evidence of spread of the tumor at the time of the diagnosis. Aggressive surgical removal to relieve some of the severe symptoms .

Glucagonoma : Glucose intolerance; migratory necrolytic erythema; weight loss; anemia;

90% malignant

Somatostatinoma :Diabetes; gallstones; secretory diarrhea

VIPoma ( verner morrison syndrome ): Cholera-like, secretory diarrhea; hypokalemia; hypochlorhydria

When a NET is suspected, imaging tests are used to locate the primary tumor and determine the presence of metastases . NETs may be difficult to localize. Contrast-enhanced CT and MRI may be used as initial tests; however, they have a low yield for small tumors. Endoscopic US is a more sensitive test for detecting small pancreatic neuroendocrine tumors. Insulinomas are not well visualized with octreotide scans because they do not possess high concentrations of somatostatin receptors...