Adenocarcinoma of the Exocrine Pancreas Flashcards
Epidemiology
- While the increasing and aging population is the most likely cause of this increase
- The risk of pancreatic cancer increases with age beyond the sixth decade; the mean age at diagnosis is 72 years.
Which rank cancer deaths in United States.
The third most common cause of cancer deaths in United States.
Hereditary risk factors associated with development of pancreatic cancer»_space; PRSS1
Familial pancreatitis
> > Mutation results in chronic pancreatitis and 40% lifetime risk of PDAC
STK11
Peutz-Jeghers syndrome
> > Mutation results in >100-fold increase in risk of PDAC
CDKN2A
Familial atypical mole and multiple melanoma syndrome
> > Mutation leads to increased risk of melanoma and >40-fold increase in risk of PDAC
CFTR
Cystic fibrosis
> > Thick secretions result in chronic pancreatitis and 30-fold increase in risk of PDAC
BRCA2
Hereditary breast and ovarian cancer
> > Mutation results in elevated risk of breast and ovarian cancer and 10-fold increase in risk of PDAC
MLH1
Lynch syndrome
> > Mismatch repair gene mutation leads to increased risk of colon cancer and eightfold increase in risk of PDAC
APC
Familial adenomatous polyposis
> > Mutation results in polyposis coli and colon cancer with fourfold increase in risk of PDAC
“Poor Souls Can Crack Bricks Making Aches”
P – PRSS1
S – STK11
C – CDKN2A
C – CFTR
B – BRCA2
M – MLH1
A – APC
RF
Smoking
Obesity
New onset Diabetes
> > elderly patients with new-onset diabetes in the presence of unusual symptoms like weight loss and abdominal symptoms, diagnosis of pancreatic cancer should be considered and may lead to early diagnosis of pancreatic cancer.
familial pancreatic cancer (FPC)
- The remaining 80% of patients with an inherited predisposition but who do not have an identifiable genetic syndrome
- Two or more first-degree relatives with pancreatic adenocarcinoma that do not fulfill the criteria of other inherited tumor syndromes with an increased risk for the development of pancreatic adenocarcinoma.
Pathogenesis of Sporadic Pancreatic Cancer
> > pathogenesis of PDAC, including PDX1, KRAS2, CDKN2A/p16, P53, and SMAD4.
Pancreatic Intraepithelial Neoplasia
PanIN is defined histologically by
» progressive abnormality of the ductal epithelium from columnar metaplasia (PanIN-1A) through carcinoma in situ (PanIN-3).
PanIN-1A, 1B, 2, and 3
PanIN-1A :
» columnar, mucin-producing ductal epithelium that maintains basally located homogeneous nuclei without atypia
PanIN-1B :
» The development of papillary architecture
PanIN-2 :
» denotes the progression from simple papillary growth to evidence of nuclear atypia
» Enlarged nuclei with nuclear crowding
PanIN-3 (carcinoma in situ) :
» complete loss of polarity and marked cytologic atypia
KRAS2 oncogene
> > activated in more than 95% of pancreatic cancers and is thought to be the initiating event in tumorigenesis
> > one of the earliest genetic abnormalities identified in the progression of PanIN to PDAC
CDKN2A/p16, P53, and SMAD4 are tumor suppressor genes
CDKN2A encodes p16 :
» which halts the cell cycle via CDK4/6 inhibition
» Its loss is seen in ~90% of PDACs and progresses from PanIN-1 (30%) to PanIN-3 (71%).
P53:
» regulating apoptosis and cell cycle arrest
» is rarely mutated in PanIN but is altered in 79% of invasive PDACs.
SMAD4 :
» part of TGF-β signaling, is lost in 78% of metastatic PDACs, but less so in early PanIN-3 (20–30%)
Courvoisier , Virchow node, and Sister Mary Joseph node
> > Courvoisier :
slow progressive occlusion more likely to result in ectasia of the organ.
> > Virchow node :
a left supraclavicular node may be palpable
> > Sister Mary Joseph node :
periumbilical lymphadenopathy may be palpable .
> > Blumer shelf
peritoneal dissemination, perirectal tumor involvement may be palpable through digital rectal examination
The left supraclavicular lymph node (Virchow node) , why not right ?
> > gastric, pancreatic, and other GI cancers :
receives lymphatic drainage via the thoracic duct, which collects lymph from most of the body except the right upper quadrant.
> > empties into the left subclavian vein near the left supraclavicular fossa
> > The right supraclavicular node drains only the right head, neck, thorax, and upper limb, so it’s less commonly affected by abdominal cancers.
careful attention should be paid to nutritional values, if surgical intervention is to be considered
prealbumin and albumin levels
Tumor markers
CEA, carbohydrate antigen 19-9 (CA 19-9), and α-fetoprotein.
Of these, CA 19-9 is most sensitive for pancreatic adenocarcinoma, with a sensitivity of approximately 79% and a specificity of 82%
A notable limitation of CA 19-9 testing
> > in the setting of periampullary tumors is the false elevation caused by biliary obstruction
10% to 15% of individuals do not have elevation of the CA 19-9 level, a finding that has been associated with
> > blood Lewis antigen–negative status and is caused by a lack of the fucosyltransferase gene.
CA-19.9 useful for
> > pretreatment evaluation and posttreatment surveillance
predictive and prognostic marker.
normalization of CA 19-9 after neoadjuvant therapy has been suggested as an important prognostic factor
use for identifying patients who will benefit from staging laparoscopy
Which type of CT required
> > For suspected periampullary disease,
a three-phase (noncontrast, arterial, and portal venous) CT scan with 3-mm slices and coronal and three-dimensional reconstruction should be routine.
seen as a hypoattenuating lesion during the portal venous phase of the imaging.
ERCP Role ?
> > Preoperative biliary decompression may increase the rate of wound infection caused by bactibilia, although overall morbidity and mortality are unchanged.
> > In modern medical practice, ERCP should be reserved for cases requiring therapeutic or palliative intervention
> > given the increased use of neoadjuvant chemotherapy approach. In such cases, use of short metal stent rather than plastic stents is recommended
EUS Role ?
- FNA has a sensitivity and specificity that are far superior to those of brush cytology,
- Evaluation of peritumoral vasculature and regional lymph nodes
- Identification of small tumors that do not appear on CT scans and for the delineation of more clearly suspicious lesions smaller than 2 cm
MRCP ?
MRCP has become useful for the investigation of cystic lesions of the pancreas, with sensitivity and specificity slightly superior to CT alone
FDG PET
> > 18F-fluorodeoxyglucose positron emission tomography (FDG PET) in combination with CT scanning has been increasingly used in the evaluation of pancreatic cancer.
> > potential benefits of FDG PET with CT, including the ability to differentiate between benign and malignant pancreas tumors (autoimmune pancreatitis vs. adenocarcinoma)
Staging?
- After biopsy confirmation, typically by EUS-FNA
- CT scanning of the abdomen and pelvis with three-phase administration of contrast material and three-dimensional reconstruction.
- Chest radiography is sufficient for the evaluation of potential pulmonary metastasis
- followed by CT of the chest if any suspicious lesions
- tumors are classified into resectable, borderline resectable, or unresectable
Resectable tumors are defined as
> > localized to the pancreas
no evidence of SMV or portal vein involvement
(i.e., no abutment, distortion, thrombus, or encasement)
preserved fat plane surrounding the SMA and celiac artery branches, including the hepatic artery.
Do you use neoadjuvant strategy ?
> > Currently, given the success of neoadjuvant strategy in the treatment of borderline resectable pancreatic cancer,
> > there is increased use of preoperative chemotherapy for the treatment of even resectable disease.
borderline resectable as tumors that exhibit one or more of the following characteristics:
- Venous involvement:
» solid tumor contact with SMV or portal vein of more than 180 degrees
» contact of less than or equal to 180 degrees with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction. - Arterial involvement:
- Hepatic artery involvement:
» solid tumor contact with common hepatic artery (abutment or encasement) without extension to the celiac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction.
- SMA involvement:
» solid tumor contact with the SMA of less than or equal to 180 degrees.
Unresectable tumors
- exhibit metastasis
(including lymph node metastasis outside the field of resection) - ascites
- vascular involvement beyond what has been detailed here
Staging laparoscopy
Indications:
- large tumors (>3 cm)
- significantly elevated CA 19-9 level (>100 U/mL)
- uncertain findings on CT
- body or tail tumors.
- clinical indicators of widespread disease
including significant weight loss, malnutrition, and pain
role and place of peritoneal cytology
> > unclear at this time
> > positive findings on peritoneal cytology have very poor prognosis and behave like patients with metastatic disease.
Surgery for Tumors of the Head of the Pancreas
pancreaticoduodenectomy
Surgical technique
- exploration of the peritoneal surfaces for evidence of metastatic disease
- A Kocher maneuver is performed to the level of the left lateral border of the aorta
- The transverse mesocolon is separated off the head of the pancreas, exposing the infrapancreatic SMV.
- The lesser sac is entered through the gastrocolic ligament
- The right gastroepiploic vein is ligated at its confluence with the SMV
- allowing the SMV to be dissected from the inferior border and posterior neck of the pancreas.
- The middle colic vein may also be sacrificed, if necessary
Surgical technique 2
- Once the infrapancreatic SMV is dissected and the head of the pancreas is fully mobilized
- the gallbladder is removed and the common hepatic duct is circumferentially dissected
- Division of the common hepatic duct allows visualization of the suprapancreatic portal vein.
- In pylorus preserving pancreaticoduodenectomy, the duodenum is divided at least 2 cm distal to the pylorus.
> The hepatic artery is exposed proximally and distally and assessed for replacement or aberrant anatomy.
> The GDA and right gastric artery are visualized.
> Before division of the GDA, the vessel is temporarily occluded, and blood flow through the distal common hepatic artery is ensured using a Doppler device - in patients with atherosclerosis of celiac origin to ensure that the hepatic blood supply is not dependent on collateral retrograde arterial flow from the SMA through the GDA
- right gastric artery and GDA are ligated and divided. If flow in the hepatic artery is interrupted by occlusion of the GDA, resection may proceed only with preservation of the GDA or arterial resection and bypass, typically as an aortohepatic conduit
Surgical technique 3
- pancreas is then divided after four-point ligation of the inferior and superior pancreaticoduodenal arteries
- jejunum is divided approximately 10 cm distal to the ligament of Treitz
- The head of the pancreas and attached small bowel are then retracted to the patient’s right, and the remaining portal vein and uncinate dissection is completed.
- With the portal vein completely free, the gland is retracted farther to the right to allow complete visualization of the uncinate process and SMA.
- The retroperitoneal tissue is dissected from the SMA, allowing complete removal of the periarterial lymphatic tissue.
- Resections that compromise less than 50% of the venous diameter can be closed primarily
- otherwise, segmental resection with primary anastomosis or interposition graft using internal jugular or femoral vein should be performed
Surgical technique 4
- some surgeons will obtain a frozen section evaluation of the pancreatic neck margin.
- pancreaticojejunostomy and hepaticojejunostomy.
- The pancreaticojejunostomy is created in two layers, anterior and posterior, with a duct-to-mucosa anastomosis
- An internal or external pancreatic stent can be left in place for ducts smaller than 5 mm
- The hepaticojejunostomy anastomosis is then created downstream from the pancreaticojejunostomy in an end-to-side fashion.
- duodeno- or gastrojejunostomy is completed
- External drains
- A feeding jejunostomy
Before division of the GDA, the vessel is temporarily occluded, Why ?
> > Asses blood flow through the distal common hepatic artery is ensured using a Doppler device.
> > For patients with atherosclerosis of celiac origin to ensure that the hepatic blood supply is not dependent on collateral retrograde arterial flow from the SMA through the GDA.
> > If flow in the hepatic artery is interrupted by occlusion of the GDA
resection may proceed only with preservation of the GDA or arterial resection and bypass, typically as an aortohepatic conduit.
If portal venous or SMV tumor involvement is encountered venous resection should be performed, How ?
> > Resections that compromise less than 50% of the venous diameter can be closed primarily
> > otherwise, segmental resection with primary anastomosis or interposition graft using internal jugular or femoral vein should be performed
Surgery for Tumors of the Body and Tail of the Pancreas
> > rarely resectable at the time of presentation, given the lack of symptoms with small tumors
> > tumor involvement of the splenic artery or vein does not preclude surgery
> > involvement of the celiac axis is a contraindication to resection.
Surgery for Tumors of the Body and Tail of the Pancreas, Approaches ?
> > distal pancreatectomy and en bloc splenectomy should be performed.
> > Distal pancreatectomy and splenectomy can be performed in a retrograde fashion whereby the spleen and pancreas are mobilized lateral to medial en bloc, thus providing access to splenic vasculature located superior and behind the pancreas.
> > Alternatively, the dissection can proceed antegrade in a medial to lateral fashion
In this approach, the pancreatic neck is encircled and divided away from the tumor early in the procedure.
This medial-to-lateral approach in combination with extensive lymph node dissection has been termed radical antegrade modular pancreatosplenectomy
Technique ?
- inspection of the peritoneal surfaces
- the gastrocolic and splenocolic ligaments and short gastric vessels are divided to expose the pancreas and spleen.
- inferior border of the pancreas is dissected
- exposing the retroperitoneal plane behind the gland
- mobilize the body and tail of the pancreas anterior to Gerota fascia
- At the superior border of the pancreas, the splenic artery is circumferentially dissected and divided at its origin from the celiac trunk
- The splenic vein is carefully dissected from the posterior wall of the pancreas at its confluence with the SMV
- distal pancreas and spleen are devascularized and the neck of the pancreas is divided.
- en bloc removal of the specimen and surrounding lymph node basin
- close the pancreatic duct remnant, with the most common being direct suture ligation or use of a linear stapling device
close the pancreatic duct remnant
» direct suture ligation or use of a linear stapling device
No difference in terms of pancreatic Fistula
morbidity after Whipple procedure
> > morbidity remains common
occurring after 30% to 50% of procedures
> > less than 2% of cases at high-volume centers Mortality
Morbidity after pancreaticoduodenectomy
Delayed gastric emptying %18
Pancreas fistula %12
Wound infection %7
Intraabdominal abscess %6
Cardiac events %3
Bile leak %2
Overall reoperation %3
Most patients experience relapse of disease in the form of
> > metastatic disease (85%)
Less commonly, local recurrence (40%)
Delayed Gastric Emptying
> > the need for prolonged nasogastric decompression or inability to tolerate oral intake is a frequent complication after pancreaticoduodenectomy, occurring 5% to 15% of the time.
> > When patients have the inability to tolerate solid foods or a prolonged nasogastric tube requirement
DO CT SCAN and UPPER SCOPE
Rule OUT stricture or other anastomotic complication, LEAK or Abscess
> > Enteral feeding with a feeding tube placed during surgery or percutaneously through endoscopy is used to maintain nutrition while waiting for stomach function to return
Pancreatic leak or pancreatic fistula
“output via an intraoperatively placed drain (or percutaneous drain) of any measurable volume on or after postoperative day 3, with amylase >3 times normal serum value,”
most predictive factor is
> > the texture of the gland, with soft fatty glands at significantly higher risk of leak
Tx ?
Drain
Rarely > Additional Drain , Re-Op
Sometimes > Completion Pancreatectomy
Other Complications
> > Anastomotic leaks from the hepaticojejunostomy and duodenojejunostomy are rare and occur after less than 5% of procedures.
> > Infectious complications
(e.g., intraabdominal abscess, wound infection) are slightly more common and may require intervention with percutaneous drainage or open wound dressing changes.
Palliative Bypass in the Case of Unresectable/Metastatic Disease
- If metastases or unresectable disease is observed once laparotomy has been performed, decision to proceed with biliary and/or gastrointestinal bypass needs to be individualized
- In the setting of carcinomatosis or multifocal metastatic disease, regardless of performance status, endoscopic intervention should be favored due to the short median survival
- If patient has had obstructive gastrointestinal symptoms or a need for placement of duodenal stent previously, it may be prudent to do gastrointestinal bypass
- patients with good functional status and low-volume metastatic disease or locally advanced disease, operative biliary bypass is a reasonable option
Pylorus-Preserving versus Non–Pylorus-Preserving Whipple Procedure
- initially proposed as a means to reduce postpancreatectomy dumping and bile reflux, which is common after a non–pylorus-preserving Whipple procedure.
Pancreaticojejunostomy Versus Pancreatogastrostomy
In cases in which the pancreatic duct is not identified, invagination of the gland into the jejunal stump or pancreatogastrostomy may be performed.
Use of Somatostatin Analogues to Reduce Pancreatic Fistula
- The efficacy of pasireotide, a somatostatin analogue with a longer half-life (11 hours for pasireotide vs. 2 hours for octreotide) and a broader binding profile (pasireotide binds to somatostatin-receptor subtypes 1, 2, 3, and 5, whereas octreotide binds only to receptor subtypes 2 and 5), in reducing pancreatic fistula, leak, or abscess of grade 3 or higher after pancreatic surgery (both pancreaticoduodenectomy and distal pancreatectomy).
Extent of Lymphadenectomy
- In addition to peripancreatic, portal, and pyloric lymph nodes
> > extended lymphadenectomy includes retrieval of hilar and retroperitoneal lymph nodes, extending from the celiac origin to the level of the inferior mesenteric artery and including all tissue between the renal hilum laterally
- no evidence to suggest improved survival after extended lymphadenectomy
Laparoscopic and Robotic Pancreaticoduodenectomy
- median length of hospital stay was shorter with the laparoscopic approach.
- a significantly higher proportion of patients had delay in delivery of adjuvant therapy with the open approach
- major morbidities that follow pancreaticoduodenectomy are not related to the size of the incision, the laparoscopic Whipple procedure has not become widely adopted
- open pancreaticoduodenectomy remains the standard of care.
Antecolic versus Retrocolic Duodenojejunostomy
antecolic duodenojejunostomy may improve gastric emptying compared with the retrocolic technique.
Drain Versus No Drain
- high frequency of pancreatic fistula after pancreatic resection and morbidity associated with uncontrolled pancreatic leak, drains are routinely used after pancreatic resections
- associated with increased rates of intraabdominal and wound infection, increased pain, and prolonged hospital stay.
Chemotherapy and Radiation Therapy
Although the use of chemotherapy is widely accepted, the usefulness of radiation therapy has been increasingly questioned.
In the United States, chemotherapy and radiation therapy are still widely used,
whereas European centers have stopped using radiation therapy as part of standard adjuvant therapy because of lack of evidence to support a survival benefit.
Chemotherapy and Radiation Therapy 2
The current NCCN guidelines recommend gemcitabine or 5-FU alone or in combination with 5-FU–based chemoradiation as adjuvant treatment after resection for PDAC.
Given the overall poor prognosis, enrollment into clinical trials is encouraged
This trial has established gemcitabine and capecitabine as the new standard for adjuvant therapy following resection for PDAC
Role of Neoadjuvant Therapy
- The administration of chemotherapy, with or without radiation therapy, before planned surgical resection for pancreatic cancer is becoming increasingly common
- Neoadjuvant therapy may provide improved selection of patients, avoiding surgery for those who progress, but also improved negative margin rates and reduced lymph node metastasis.
- for individuals with significant SMV–portal vein involvement (>180 degrees or short-segment encasement) or hepatic arterial or SMA abutment (<180 degrees), neoadjuvant therapy may play an important role in identifying the subset of patients most likely to derive benefit from aggressive multimodality therapy, including surgical resection with vascular reconstruction
Chemotherapy for Metastatic Pancreatic Adenocarcinoma
- More than 80% of patients with pancreatic cancer present with locally advanced or metastatic disease and are primarily managed with chemotherapy
- Gemcitabine has been the standard of care for the treatment of metastatic pancreatic cancer since the late 1990s
- FOLFIRINOX is being used as the neoadjuvant regimen of choice in patients with borderline resectable pancreatic cancer and good performance status who can tolerate this aggressive regimen
Biliary Obstruction
- ERCP with metal stent placement provides excellent palliation of jaundice
- In patients for whom endoscopic palliation is impossible, percutaneous biliary drainage with subsequent internalization may be required.
- For patients who are found at laparotomy to have unresectable disease or those for whom nonsurgical measures have failed, a surgical biliary-enteric bypass may be performed by Roux-en-Y hepaticojejunostomy, with excellent long-term patency.
Gastric Outlet Obstruction
- endoscopic luminal stenting should be carried out.
- limited in its ability to provide long-term patency
- patients who are found to have unresectable cancer at the time of laparotomy may benefit from preventive gastrojejunostomy
- For patients who require surgical intervention, a double bypass consisting of a Roux-en-Y hepaticojejunostomy and gastrojejunostomy may be performed.
Pain Relief
> > The initial management of pain may include antiinflammatories or long-acting opioids, taken orally or through a cutaneous patch. For patients with pain that is not well controlled or who suffer side effects of narcotic use, celiac nerve block should be considered.
> > The procedure involves injecting a combination of 3 mL of 0.25% bupivacaine and 10 mL of absolute alcohol into each celiac plexus.
