pancreatic adenocarcinoma

Etiology

Risk factors:

• cigarette smoking, relative risk 1.5
• diet: high in meat & fat, low in vegetable & fruit
• chronic pancreatitis, standardized incidence ratio 26.3
• diabetes mellitus
• obesity
• blood group other than type O
• chronic chemical exposure
  • 2-naphthylamine
  • benzidine
  • gasoline derivatives
• hereditary neoplastic syndrome (see genetics)
• age > 60 years

Epidemiology

• incidence in US is 10 in 100,000
• male:female ratio 1.3
• rare before 40 years of age; median age = 71 years

Pathology

• ductal adenocarcinoma
  • 90% of pancreatic cancers are ductal adenocarcinomas
• majority of pancreatic adenocarcinomas are moderately to poorly differentiated
• extensive stromal reaction (desmoplasia)
• hypovascular & hypoxic microenvironment
• reprogramming of cellular metabolism
• evasion of tumor immunity
• local invasion into branches of the celiac artery or superior mesenteric artery
• occlusion of the superior mesenteric vein
• metastases typically to liver, peritoneum & occasionally to lung

Genetics

• hereditary neoplastic syndromes
  • hereditary pancreatitis
    • PRSS1, SPINK1
  • Peutz-Jehgers syndrome: STK11
  • familial atypical mole & melanoma syndrome: p16
  • Lynch syndrome
    • MLH1, MSH2, MSH6
  • Li-Fraumeni syndrome: p53
  • ataxia telangiectasia: ATM
• activating mutations in KRAS (>90%)
• mutations in p16ink4A (80-95%)
• mutational inactivation of the CDKN2A, p53 (50-75%), & SMAD4 (55%)
• mutations in PRAD1, Ki-67 & BRCA2
• also see pancreatic cancer

Clinical manifestations

• jaundice*: majority of tumors occur in head of pancreas
• weight loss*
• pain
  • abdominal or back
  • worsened by lying down
  • relieved by sitting of crouching
• superficial thrombophlebitis (Trousseau's sign) 5%
• pancreatitis may result from obstruction of pancreatic duct
• glucose intolerance in 80%
• depression
• variceal hemorrhage (rare), splenic or portal vein
• hepatomegaly with jaundice in advanced disease or metastases
• portal hypertension may lead to ascites or peripheral edema

* most common

Laboratory

• serum chemistries may be abnormal, but are non-specific
  • serum glucose
  • serum amylase
  • serum lipase
  • serum alkaline phosphatase
  • serum transaminases
• mucinous glycoprotein levels are non-specific
  • serum CA 19-9:
    • serum level > 800 ug/mL indicates a poor prognosis
  • serum CA 50
• serum C-reactive protein (CRP)
  • serum level > 200 mg/dL indicates a poor prognosis
• genomic sequencing for patients that progress on standard therapy
• multiplex IMMray PanCan-d assay has specificity of 98% & sensitivity of 87% in identifying pancreatic ductal adenocarcinoma among patients at increased genetic or familial risk
• urine biomarker panel (LYVE1, REG1B & TFF1) alone & in combination with plasma CA19-9 cab detect pancreatic adenocarcinoma up to 2 years prior to diagnosis

Diagnostic procedures

• abdominal ultrasound is best initial diagnostic test
• endoscopic ultrasound with fine-needle aspiration has similar accuracy as CT in assessing resectability in patients whose disease is unstaged & has a slight advantage over CT with respect to staging (lower chance is underestimating size of tumor)

Radiology

• abdominal CT for staging or equivocal ultrasound
• MRI has no advantage over CT
• ultrasound or CT-guided percutaneous needle biopsy
• endoscopic ultrasound with transendoscopic fine-needle biopsy of lymph nodes is useful for staging
• some surgeons use angiography to evaluate resectability

Staging

• high resolution multidetector CT
  • 5-7 mm sections
  • oral contrast
• endoscopic ultrasound
• stages:
  • localized, resectable disease
  • locally advanced disease
  • metastatic disease

* most patients initially diagnosed with stage I or II pancreatic ductal adenocarcinoma are upstaged following histopathology, potentially due to missed lymph nodes

Differential diagnosis

• chronic pancreatitis
• cholecystitis
• irritable bowel syndrome
• retroperitoneal lymphoma or sarcoma
• carcinoma of the duodenum
• common bile duct stones & strictures
• peptic ulcer disease
• depression
• ampullary carcinoma (better prognosis)
• metastatic disease to the pancreas &/or retroperitoneum

Management

• surgery is the only curative treatment
  • 15-20% are surgical candidates
    • tumor butting against the superior mesenteric artery prevents resection
  • pancreatoduodenectomy (Whipple's operation) is most popular procedure
  • pre or postoperative radiotherapy with or without chemotherapy (5-fluorouracil or gemcitabine)
  • neoadjuvant chemotherapy is the standard of care for borderline resectable & locally advanced pancreatic ductal adenocarcinoma
    • adjuvant chemotherapy may prolong survival
  • combination chemotherapy
    • FOLFIRINOX
      • adjuvant FOLFIRINOX is the standard of care after pancreatic resection
        • results in longer survival than gemcitabine
    • gemcitabine + nab-paclitaxel
    • can lengthen survival from 3-6 months to 10-11 months
    • erlotinib may add 2-weeks additional overall survival to gemcitabine therapy
  • perioperative chemotherapy does not improve overall 2-year survival in resected pancreatic adenocarcinoma
  • palliative surgery with unresectable tumor
    • cholecystojejunostomy for jaundice
    • gastrojejunostomy for duodenal obstruction
    • stents placed by ERCP
    • mean survival after palliative surgery is 5-6 months
• unresectable or metastatic disease (stage 3 or 4)
  • combination adjuvant chemotherapy
    • FOLFIRINOX
    • gemcitabine + nab-paclitaxel
  • local radiation therapy may be an option
  • conversion from unresectable to resectable does occur
  • neoadjuvant FOLFIRINOX with individualized chemoradiotherapy for borderline resectable cancer
    • FOLFIRINOX for 8 cycles followed by restaging
    • chemoradiotherapy (5 Gy x 5 with protons) with capecitabine if resolution of vascular involvement
    • chemoradiotherapy (50.4 Gy in 28 fractions) with fluorouracil or capecitabine if vascular involvement persists
  • neoadjuvant FOLFIRINOX, losartan, followed by chemoradiotherapy for locally advanced pancreatic adenocarcinoma
• pain management
  • acetaminophen
  • non-steroidal anti-inflammatory drugs (NSAIDs)
  • morphine
  • codeine
  • percutaneous celiac plexus block
• malabsorption with steatorrhea may be treated with pancreatic enzyme therapy with meals
• prognosis:
  • 2 year survival 10%
  • 5 year survival 3%
  • 5-22% have resectable tumors, 15% survive 5 years
  • 5-year survival for node-negative disease is 25-30%; for node-positive disease ~10%
  • life expectancy for unresectable tumors in 8-12 months
    • same ref says average survival is 4-6 months
• follow-up
  • history & physical every 3-6 months for 2 years, then annually
  • abdominal CT every 3-6 months for 2 years, then annually
  • serum CA 19.9 every 3-6 months for 2 years, then annually

More general terms

• exocrine pancreatic neoplasm
• adenocarcinoma

Additional terms

• cancer antigen CA 19-9 (carbohydrate antigen 19-9) in serum
• cancer antigen CA 50 in serum
• pancreatic adenocarcinoma genotyping
• SMAD4/MADH4; mothers against decapentaplegic homolog 4; mothers against DPP homolog 4; MAD homolog 4; SMAD family member 4; SMAD 4; smad4; hSMAD4; deletion target in pancreatic carcinoma 4 (SMAD4, DPC4, MADH4)

Database

• OMIM: https://mirror.omim.org/entry/260350