Special Surgery 15. Malignant Diseases of the Pancreas: Curative and Palliative, Surgical and Interventional Options

I. Types, Risk Factors and Spread

Main Types

1. Exocrine Pancreatic Tumors

Pancreatic ductal adenocarcinoma:

Most common pancreatic malignancy, about 90%
Arises from exocrine ductal epithelium
Very aggressive, usually late diagnosis

Acinar cell carcinoma: rare exocrine tumor
Undifferentiated carcinoma: rare, aggressive
Cystic neoplasms with malignant potential:

IPMN = intraductal papillary mucinous neoplasm
Mucinous cystic neoplasm
Mucinous cystadenocarcinoma

2. Endocrine Pancreatic Tumors

Pancreatic neuroendocrine tumors (pNET)
Can be benign or malignant
Functional tumors produce hormone symptoms:

Insulinoma → hypoglycemia
Gastrinoma → Zollinger-Ellison syndrome, recurrent ulcers
Glucagonoma → diabetes, weight loss, necrolytic migratory erythema
VIPoma → watery diarrhea, hypokalemia, achlorhydria

Non-functional pNET often presents late as mass/metastasis

Risk Factors for Pancreatic Ductal Adenocarcinoma

Age > 50 years, risk rises with age
Smoking: strongest modifiable risk factor
Chronic pancreatitis
Obesity
Diabetes mellitus, especially new-onset diabetes in older patient
Family history / genetic predisposition:

BRCA1/BRCA2, PALB2
CDKN2A / familial atypical multiple mole melanoma syndrome
Lynch syndrome
Peutz-Jeghers syndrome
Hereditary pancreatitis

Alcohol indirectly through chronic pancreatitis

Localization

Head of pancreas: most common, about 60-70%
Body/tail: often later symptoms and larger tumor at diagnosis
Diffuse/multifocal involvement is less common but possible

Spread

Direct invasion:

Duodenum
Stomach/colon in advanced disease
Portal vein / superior mesenteric vein
Superior mesenteric artery, celiac axis, common hepatic artery

Lymphatic spread:

Peripancreatic, hepatoduodenal ligament, celiac and SMA nodes
Virchow node in advanced disease
Sister Mary Joseph nodule: periumbilical metastasis

Hematogenous spread:

Liver most common
Lung
Bone and other organs

Peritoneal seeding can occur

II. Symptoms and Diagnosis

Clinical Features

Early stage often asymptomatic
Constitutional symptoms:

Weight loss
Anorexia
Fatigue
Cachexia

Head of pancreas tumor:

Painless progressive jaundice
Dark urine
Acholic/pale stool
Pruritus
Cholangitis if infected obstruction

Courvoisier sign:

Palpable, painless, enlarged gallbladder with obstructive jaundice
Suggests malignant obstruction of distal biliary tract/pancreatic head rather than chronic gallstone obstruction

Body/tail tumor:

Epigastric pain radiating to back, belt-like
Often late because no early bile duct obstruction
Can invade celiac plexus → severe back pain

New-onset diabetes in elderly or worsening diabetes
Exocrine insufficiency: steatorrhea, malabsorption, weight loss
Trousseau syndrome: paraneoplastic migratory thrombophlebitis
Depression can precede diagnosis in some patients

Laboratory Tests

Cholestatic pattern if bile duct obstruction:

Increased bilirubin, mainly direct/conjugated
Increased ALP and GGT
AST/GOT and ALT/GPT can increase

Pancreatic enzymes can be increased but are not diagnostic for cancer
Hyperglycemia / new diabetes
CA 19-9:

Useful for prognosis and follow-up if elevated
Not diagnostic alone
Can be falsely elevated in obstructive jaundice/cholangitis
Can be falsely negative in Lewis antigen-negative patients

CEA is less specific; can be supportive in selected cases

Imaging

Ultrasound

Often first test in jaundiced patient
Shows dilated intra/extrahepatic bile ducts
May show pancreatic head mass, but sensitivity limited by bowel gas/body habitus
Good for detecting liver metastases and gallstones, but not definitive staging

Pancreas-Protocol Contrast CT

First-line test for diagnosis and staging when pancreatic cancer suspected
Multiphasic thin-slice CT evaluates:

Primary tumor size/location
Vascular involvement: SMV/PV, SMA, celiac axis, common hepatic artery
Local invasion
Liver/peritoneal metastases
Resectability category

MRI / MRCP

Useful if CT equivocal or contrast allergy/renal issue
Better characterization of liver lesions
MRCP maps pancreatic and biliary ducts
Helpful for cystic neoplasms such as IPMN

EUS

Endoscopic ultrasound
High sensitivity for small pancreatic masses
Local staging and vascular/lymph node assessment
EUS-guided FNA/core biopsy:

Preferred tissue diagnosis method when needed
Needed before neoadjuvant therapy, chemotherapy, or if diagnosis uncertain
May be omitted before upfront surgery if imaging shows clearly resectable classic pancreatic cancer and MDT agrees

ERCP

Mainly therapeutic, not primary diagnostic staging tool
Indications:

Biliary stenting for obstructive jaundice/cholangitis
Brush cytology/biopsy if needed
Preoperative drainage only selectively: cholangitis, severe symptomatic jaundice, delayed surgery, or neoadjuvant therapy planned

Other Staging

Chest CT to detect lung metastases
PET-CT in selected cases when occult metastasis is suspected; not routine replacement for CT/MRI
Diagnostic laparoscopy can detect occult peritoneal/liver surface metastases in high-risk patients:

Large body/tail tumors
Very high CA 19-9
Borderline resectable disease
Suspicious but unconfirmed metastatic disease

III. Curative Treatment

Resectability Categories

Category	Core Idea	Treatment Logic
Resectable	No distant metastasis and no major arterial involvement; venous involvement absent or reconstructable depending on criteria	Surgery-first or neoadjuvant therapy depending on center/risk, then adjuvant chemotherapy
Borderline resectable	Limited vessel contact where R0 resection is uncertain but possible after response/reconstruction	Neoadjuvant therapy → restaging → surgery if no progression
Locally advanced unresectable	Major arterial encasement or unreconstructable venous involvement, no distant metastasis	Systemic therapy +/- chemoradiation/local palliation; conversion surgery only selected responders
Metastatic	Distant organ/peritoneal metastasis	Systemic/palliative therapy

General Curative Principles

Only possible in about 15-20% of patients at diagnosis
Goal: R0 resection + regional lymphadenectomy + systemic therapy
Pancreatic cancer is systemic early → chemotherapy is essential even after complete resection
Decision in pancreatic MDT / onco-team

Neoadjuvant Therapy

Indications:

Borderline resectable cancer
Selected high-risk resectable tumors: very high CA 19-9, large tumor, suspicious nodes, severe symptoms
Locally advanced disease with possible conversion intent in selected patients

Benefits:

Treats micrometastatic disease early
Selects out rapidly progressive disease before major surgery
Can increase R0 resection chance
Can downstage vessel involvement

Regimens: modified FOLFIRINOX in fit patients, gemcitabine/nab-paclitaxel alternative depending on protocol and fitness
Radiotherapy/chemoradiotherapy: selected cases, not automatic for all

Surgical Procedures

Pancreaticoduodenectomy / Whipple Procedure

For tumors in pancreatic head, uncinate process, periampullary region
Resection includes:

Pancreatic head
Duodenum
Gallbladder
Distal common bile duct
Often distal stomach/antrum in classical Whipple, or pylorus-preserving variant
Regional lymphadenectomy

Reconstruction:

Pancreaticojejunostomy or pancreaticogastrostomy
Hepaticojejunostomy
Gastrojejunostomy or duodenojejunostomy

Distal Pancreatectomy

For body/tail tumors
Usually includes splenectomy for adenocarcinoma because of lymphatic drainage
Spleen-preserving distal pancreatectomy is mainly for selected benign/low-grade tumors, not typical pancreatic ductal adenocarcinoma

Total Pancreatectomy

Rare
Indications:

Multifocal disease/IPMN involving whole gland
Positive margins not otherwise clearable
Complex anatomy or high-risk remnant in selected cases

Consequence: complete endocrine and exocrine insufficiency → brittle diabetes + lifelong enzyme replacement

Vascular Resection

SMV/portal vein resection and reconstruction can be done in selected cases to achieve R0 resection
Arterial resection is much more selective/high-risk and not routine
Major unreconstructable vascular invasion generally means unresectable disease

Adjuvant Therapy

Adjuvant chemotherapy improves survival after resection
Fit patients: modified FOLFIRINOX commonly preferred
Less fit/elderly patients: gemcitabine-based treatment, e.g. gemcitabine + capecitabine or gemcitabine alone depending on tolerance
Aim for about 6 months total systemic therapy, adjusted to neoadjuvant treatment and recovery
Adjuvant chemoradiotherapy is selective, e.g. margin-positive/local-control concern depending on protocol

Complications of Pancreatic Surgery

Pancreatic fistula / leak
Delayed gastric emptying
Post-pancreatectomy hemorrhage
Intra-abdominal abscess
Bile leak
Wound infection
Diabetes mellitus
Exocrine pancreatic insufficiency and malnutrition

IV. Palliative and Interventional Options

Systemic Therapy for Unresectable / Metastatic Disease

Goals: prolong survival, relieve symptoms, maintain quality of life
Fit patient:

FOLFIRINOX / modified FOLFIRINOX
NALIRIFOX is an option in some current protocols
Gemcitabine + nab-paclitaxel

Frail/elderly patient:

Gemcitabine-based less intensive therapy
Best supportive care if chemotherapy risk exceeds benefit

Targeted/immunotherapy selected by biomarkers:

BRCA/PALB2 mutation → platinum sensitivity; PARP inhibitor maintenance may be considered after platinum response in metastatic disease
MSI-high/dMMR rare → immune checkpoint inhibitor
NTRK/RET/ALK and other rare actionable alterations depending on molecular testing

Biliary Obstruction Palliation

First-line: ERCP with biliary stent
Metal stent preferred when longer survival expected or neoadjuvant therapy planned
Plastic stent can be used for short-term/uncertain situations
Percutaneous transhepatic biliary drainage if ERCP fails or anatomy impossible
Endoscopic ultrasound-guided biliary drainage in expert centers after failed ERCP
Surgical biliary bypass if endoscopic/percutaneous drainage fails or during laparotomy when unresectability is found:

Hepaticojejunostomy
Choledochojejunostomy
Cholecystojejunostomy only if cystic duct is patent and anatomy suitable; less reliable if tumor obstructs cystic duct/common hepatic duct

Gastric Outlet / Duodenal Obstruction Palliation

Symptoms: vomiting, early satiety, inability to tolerate oral intake
Endoscopic duodenal self-expanding metal stent:

Rapid symptom relief
Useful in limited life expectancy or high surgical risk

Surgical gastrojejunostomy:

More durable bypass
Used if longer expected survival, fit patient, or obstruction found during surgical exploration

EUS-guided gastroenterostomy is an option in specialized centers

Pain Palliation

Stepwise analgesia, often opioids required
Celiac plexus block/neurolysis:

Useful for severe pancreatic cancer pain radiating to back
Can be EUS-guided or percutaneous
Reduces opioid requirement in selected patients

Palliative radiotherapy can help local pain/bleeding in selected locally advanced cases

Nutritional and Supportive Care

Dietitian involvement early
Pancreatic enzyme replacement if exocrine insufficiency/steatorrhea or after pancreatic resection
Diabetes management
Treat pruritus/cholestasis
Antiemetics, appetite/nutrition support
VTE prophylaxis/treatment: pancreatic cancer has high thrombosis risk
Psychological and palliative care services should be integrated early

Pancreatic Neuroendocrine Tumor Treatment

Localized resectable pNET:

Enucleation for selected small benign-appearing insulinoma away from pancreatic duct
Formal pancreatic resection for larger, malignant-risk or duct-adjacent tumors
Pancreaticoduodenectomy for head tumors when needed
Distal pancreatectomy for body/tail tumors

Metastatic/advanced pNET:

Somatostatin analogues
Targeted therapy such as everolimus or sunitinib
Peptide receptor radionuclide therapy (PRRT) if somatostatin receptor-positive
Liver-directed therapy for liver-dominant metastases
Systemic chemotherapy for high-grade/aggressive disease

Prognosis

Overall prognosis is poor because most patients present late
Better prognosis if:

R0 resection possible
No lymph node involvement
Good performance status
Good response to systemic therapy

Metastatic pancreatic ductal adenocarcinoma remains incurable in usual practice; treatment is palliative/systemic