Exocrine Pancreatic Cancer

Pancreatic cancer, consisting mostly of invasive pancreatic ductal adenocarcinoma (PDAC), arises from the ductal cells of the exocrine pancreas and is the 4th leading cause of cancer-related deaths in the United States. Pancreatic cancer has the highest mortality rate among the major cancers, with a 5-year survival rate of only 8%–10%. Clinical presentation includes symptoms of abdominal pain, jaundice, and weight loss. Diagnosis is made by CT, MRI, and endoscopic ultrasonography (EUS). Management by surgical resection, usually with neoadjuvant or adjuvant chemotherapy, provides the only chance for cure in the 15%–20% of patients who have resectable disease at the time of diagnosis. Other rare malignant tumors arising from the exocrine pancreas are acinar cell carcinoma and pancreatoblastoma.

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Overview

Classification

  • 95% are from the exocrine pancreas; most are invasive pancreatic ductal adenocarcinoma (PDACs):
    • Arise from ductal epithelial cells
    • Highest mortality rate of any major cancer
    • 10%–15% are associated with hereditary syndromes.
  • 1% of neoplasms from the exocrine pancreas are acinar carcinomas:
    • Arise from the acinar cells
    • Can produce tryptase and lipase → metastatic fat necrosis
  • < 1% of neoplasms from the exocrine pancreas are pancreatoblastoma (malignant):
    • Mostly in children
    • Shows diverse tissue differentiation

Epidemiology

  • 4th leading cause of cancer-related deaths in the United States
  • Poor survival rate: Only 15%–20% of patients are surgical candidates due to late presentation.
    • The 5-year survival rate is 30% if node negative.
    • The 5-year survival rate is 10% if node positive at the time of surgery.
  • Incidence: 3.2% of all new cancer cases and 7.2% of all cancer deaths
  • 11th leading cause of death worldwide
  • Most common age group at diagnosis: 65–74 years
  • Gender/ethnicity disparities: men > women; blacks > whites

Etiology

  • Nonhereditary risk factors:
    • Smoking: greatest risk factor, causing 30% of cases
    • Older age: 70 years is the mean age at diagnosis.
    • Chronic pancreatitis
    • Diabetes mellitus (PDAC can also cause diabetes mellitus)
    • Obesity 
    • Physical inactivity
    • Diet: 
      • Eating well-done barbecued meat
      • Drinking sugary carbonated beverages
    • Male gender
    • African heritage
    • Weak association between Helicobacter pylori infection and pancreatic cancer
  • Decreased risk of PDAC: high intake of fruits and vegetables 
  • Hereditary/genetic factors in 10%–15% of all pancreatic cancers: 
Table: Hereditary/genetic factors of exocrine pancreatic cancer
Hereditary/genetic factorsGerm-line mutationsMaximum increased lifetime risk (approximate)
Peutz-Jeghers syndrome (PJS)STKII132
Hereditary pancreatitisPRSS1, others53
Familial atypical multiple mole melanoma (FAMMM)p16/CDKN2A38
Family history (increases with the number of 1st-degree relatives and if cancer < 55 years)Unknown32
Lynch syndromeMismatched repair genes30
Familial breast/ovarian cancerBRCA210
Familial breast cancer, othersPALB26
Ataxia-telangiectasiaATMNot yet established
Endocrine cells and exocrine acinar cells in pancreas

The pancreas has many functions, served by the endocrine cells in the islets of Langerhans and the exocrine acinar cells. Pancreatic cancer may arise from any of these and disrupt any of their functions.

Image: “2424 Exocrine and Endocrine Pancreas” by OpenStax College. License: CC BY 3.0

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Precursors and Pathology

Precursors to PDAC

  • Pancreatic intraepithelial neoplasia (PanIN) precede 90% of PDACs:
    • Telomere shortening occurs in cells of small ducts.
    • Mutations of the oncogene KRAS in > 90% accumulate and transition into invasive PDAC.
  • Cystic mucinous neoplasms:
    • 30% are associated with invasive PDAC.
    • 95% in woman
    • Found in the tail of the pancreas
    • Ovarian-type stroma
  • Intraductal papillary mucinous neoplasms (IPMNs):
    • Involve mostly the larger main ducts of the head of the pancreas
    • Men > women
    • Multifocal in 20%
    • GNAS proto-oncogene mutations in 75%

Pathology

  • Site frequencies: 
    • 60% head of the pancreas
    • 15% body
    • 5% tail
    • 20% entire pancreas
  • Microscopic pathology: adenocarcinomas that recapitulate normal ductal epithelium have extreme invasiveness into peripancreatic tissues and organs, the peritoneum, perineural spaces, and blood vessels.
  • Gross pathology:
    • Adenocarcinomas have the ability to provoke an intense fibrous (desmoplastic) response.
    • Hard, stellate, gray-white, poorly defined masses
    • If in the head of the pancreas: 50% will obstruct the distal common bile duct → painful obstructive jaundice
  • Metastases: 
    • Lymph nodes
    • Liver
    • Lungs
Surgical specimen of unresectable pancreatic carcinoma and H&E staining

Left image: surgical specimen of an initially unresectable pancreatic carcinoma after chemoradiotherapy
Right image: H&E staining showed the residual cancer cells present at the area encircled with the broken line.

Image: “Histopathological mapping on the macroscopic section at the plexus around the CA” by Takano H, Tsuchikawa T, Nakamura T, Okamura K, Shichinohe T, Hirano S. License: CC BY 4.0

Clinical Presentation

Pancreatic cancer is usually discovered late because of the retroperitoneal position of the pancreas.

  • If cancer is in the pancreatic head, it can cause:
    • Painless obstructive jaundice: 
      • Due to obstruction of common bile duct
      • Associated with pruritus and light-colored stools
    • Courvoisier sign: enlarged, palpable, nontender gallbladder
  • If cancer is in the body and tail, it can cause splenic vein obstruction, leading to:
    • Splenomegaly
    • Gastric and esophageal varices due to left portal hypertension
    • GI hemorrhage
  • Pain:
    • Severe
    • In upper abdomen with radiation to the back
    • Late symptom
  • Hypercoagulable state:
    • 30%–50% PDACs, compared to 10% for all cancers, due to:
      • Platelet-activating factors
      • Procoagulants from the carcinoma 
      • Necrotic products
    • May cause migratory superficial thrombophlebitis (Trousseau syndrome of malignancy = cancer-associated hypercoagulation disorder)
    • May also cause deep vein thrombosis (DVT) → pulmonary emboli (frequent cause of death)
  • Symptoms of advanced disease: 
    • Weight loss
    • Anorexia
    • Generalized malaise
    • Pancreatogenic diabetes mellitus 
    • Malabsorption: due to pancreatic exocrine insufficiency → bloating, gas, greasy stools
    • Virchow’s node: palpable supraclavicular lymph node (usually on the left side)
    • Sister Mary Joseph’s nodule: periumbilical subcutaneous metastatic nodule

Diagnosis

Imaging and biopsy are indicated for patients with suspected PDAC (pain, weight loss, jaundice).

  • Imaging: multiphasic CT with pancreatic cancer protocol 
    • If a mass lesion is found in the pancreas → evaluate for metastatic disease using PET scanning and/or multiphase CT scan of chest and pelvis.
    • If no mass lesion and no metastatic disease identified → perform endoscopic retrograde cholangiopancreatography (ERCP) or MRCP:
      • If mass or bile duct stricture is seen → biopsy
      • If no lesion is identified → follow clinically
  • Biopsy:
    • Histologic diagnosis is needed for molecular testing to guide therapy.
    • Core needle biopsies of a tumor in the pancreas can be performed: 
      • By EUS
      • By biopsy of tumor in the lymph node, liver, or other metastatic site
    • Serum tumor markers are for following patient progress, not screening, except for those with hereditary risk:
      • CA19-9
      • CEA
      • CA 125
  • Clinical staging: 
    • TNM system by the American Joint Commission on Cancer
    • Laparoscopy is advised by some physicians before definitive surgery to directly rule out metastatic disease.

Management and Prognosis

Approximately 80%–85% of PDAC tumors are not resectable at the time of presentation.

  • Overall 5-year survival rate: 8%–10%
  • Surgically resectable disease: no invasion of vessels or metastatic disease
    • About 15%–20% of patients diagnosed with PDAC are candidates for surgery.
    • Procedure depends on location:
      • If head or uncinate process → pylorus-sparing pancreaticoduodenectomy 
      • If body or tail → distal pancreatectomy
    • Neoadjuvant or adjuvant chemotherapy 
    • Median survival: 18–23 months
  • Locally advanced disease: vessels involved but no distant metastases
    • Chemotherapy alone or chemoradiotherapy
    • Median survival: 6–10 months
  • Distant metastatic disease:
    • Systemic chemotherapy
    • Median survival: 8–13 months
  • Chemotherapeutic agents and other potential factors influencing survival: 
    • Response rates are generally < 20%.
    • 1st-line therapy: FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin)
    • The most active single agents: gemcitabine and 5-fluorouracil
    • Molecular testing to detect actionable genomic alterations is needed to enter into clinical trials of targeted therapies:
      • Microsatellite instability/mismatch repair deficiency
      • BRCA mutations
      • NTRK gene fusions 
  • Palliative care for unresectable disease:
    • If jaundiced and life expectancy is > 6–7 months:
      • Endoscopic placement of a bile duct stent
      • Possible surgical bypass because of complications associated with stents
    • Pain control:
      • Analgesics, usually opioids
      • Splanchnic (celiac) block if necessary
    • Pruritus not relieved by stent or bypass: oral cholestyramine 
    • Pancreatic enzyme supplementation: as needed if there is exocrine insufficiency
    • Diabetes mellitus: treat to control hyperglycemia
    • Prevention in those with hereditary types of PDAC: 
      • Annual surveillance by abdominal ultrasound or MRI
      • CA19-9 serum levels
Whipple Pancreaticoduodenectomy

Whipple procedure: pancreaticoduodenectomy

Image by Lecturio. License: CC BY-NC-SA 4.0

Differential Diagnosis

  • Acinar cell carcinoma: a rare primary malignant exocrine gland tumor that produces exocrine enzymes such as trypsin and lipase. The enzymes can cause a metastatic fat necrosis syndrome due to lipase release in the circulation. Such malignancies can occur in children, and there is a better prognosis than with PDAC.
  • Pancreatoblastoma: a rare primary malignant exocrine gland tumor seen mostly in children. The histology shows multiple lines of differentiation (acinar, ductal, mesenchymal, neuroendocrine) and squamoid nests mixed with acinar cells. The prognosis is relatively good.
  • Pancreatic neuroendocrine tumors (PanNETs, islet cell tumors): arise from the endocrine pancreas. Pancreatic neuroendocrine tumors comprise 2% of all pancreatic neoplasms and resemble neuroendocrine tumors elsewhere in the alimentary tract. The tumors may be single or multiple and benign or malignant, may produce pancreatic hormones (e.g., insulin, glucagon, gastrin, others), or be nonfunctional.
  • Painful obstructive jaundice: usually related to gallstones with bile duct infection and fever, while painless obstructive jaundice tends to be related to a tumor in the head of the pancreas, at least early in its course. 
  • Chronic pancreatitis: can present with similar symptoms as PDAC, although PDAC can be associated with pancreatitis. Clinicoradiologic findings aid in the diagnosis, but EUS with core needle biopsy may be necessary.
  • Metastases to the pancreas: can present with similar clinical and radiographic features as pancreatic cancer. Metastases are usually multiple throughout the body, and the primary site is usually known or due to primary lung cancer. If the diagnosis is uncertain, an EUS with biopsy may be required.
  • Congenital cyst: unilocular, thin-walled cyst due to anomalous pancreatic duct development. Sizes ranges from microscopic to 5 cm. Congenital cysts are lined with cuboidal or flattened epithelium and filled with clear serous fluid. The cysts may be sporadic or part of inherited conditions such as autosomal-dominant polycystic kidney disease (PKD) and Von Hippel–Lindau disease (VHL).
  • Neoplastic pancreatic cyst: an epithelium-lined cyst that is filled with serous or mucinous fluid and can mimic PDAC. Thirty percent of mucinous cysts are associated with PDAC. Diagnosis is made by endoscopic ultrasound with fine-needle aspiration.

References

  1. Maitra, A. (2020). In Kumar, V, Abbas, AK., & Aster, JC (Eds.), Robbins & Cotran Pathologic Basis of Disease. 10th ed. pp. 890–893, and 1112–1114. Elsevier.
  2. Fernandez-del Castillo, C, & Jimenez, RE. (2021). Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer. UpToDate. Retrieved July 18, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-exocrine-pancreatic-cancer
  3. Von Hoff, DD. (2018). Pancreatic Cancer. In Jameson, J.L., et al. (Ed.), Harrison’s Principles of Internal Medicine 20th ed. Vol 1. pp. 591–595. McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192016042
  4. Nguyen, M. (2021). Pancreatic cancer. In MSD Manual Professional Edition. Retrieved July 18, 2021, from https://www.msdmanuals.com/professional/gastrointestinal-disorders/tumors-of-the-gastrointestinal-tract/pancreatic-cancer

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