- Clinical science
Pancreatic cancer is the fourth leading cause of cancer deaths in the US and typically affects older individuals in the sixth to eighth decades of life. Underlying risk factors include smoking, obesity, alcohol consumption, and chronic pancreatitis. Pancreatic carcinomas are mostly ductal adenocarcinomas and frequently located in the pancreatic head. The disease is commonly diagnosed at an advanced stage because of the late onset of clinical features (e.g., epigastric pain, painless jaundice, and weight loss). In many cases, the tumor has already spread to other organs (mainly the liver) when it is diagnosed. Treatment is often palliative as surgical resection is only possible in approx. 15% of cases. The most commonly used surgical technique is the pancreaticoduodenectomy (“Whipple procedure”). Five-year survival rates range from 1–20% depending on the extent, spread, and resectability of the tumor.
- Sex: ♂ > ♀
- Age of onset: 60–80 years
- More common in African Americans
- Accounts for ∼ 3% of all cancers in the US and ∼ 7% of cancer deaths
- The average lifetime risk: ∼ 1.5%
Epidemiological data refers to the US, unless otherwise specified.
- Chronic pancreatitis
- High alcohol consumption
- Type 2 diabetes
- Occupational exposure to chemicals used in the dry cleaning and metal working industries
- Cirrhosis of the liver
- H. pylori infection; excess stomach acid
- Inherited genetic syndromes (10% of pancreatic cancers)
- Familial pancreatic carcinoma
- Familial pancreatitis (mutations in the PRSS1 gene)
- Peutz-Jeghers syndrome
- Familial atypical multiple mole melanoma (FAMMM) syndrome
- Hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutations)
- Von-Hippel-Lindau syndrome
- Neurofibromatosis type 1
- Multiple endocrine neoplasia type 1
TNM classification for pancreatic cancer
|T1||Tumor limited to the pancreas: extent of tumor ≤ 2 cm|
|T2||Tumor limited to the pancreas: extent of tumor > 2 cm|
|T3||Tumor extends beyond the pancreas but not into major blood vessels or nerves|
|T4||Tumor grows into nearby large blood vessels or nerves|
|N1||The cancer has spread to nearby lymph nodes|
|M1||The cancer has spread to distant lymph nodes or to distant organs|
- Often no early signs present!
- Belt-shaped epigastric pain which may radiate to the back
- Weight loss, nausea, weakness, poor appetite
- Diarrhea (possibly steatorrhea secondary to exocrine pancreatic insufficiency)
- Superficial thrombophlebitis (in 10% of cases, also called Trousseau syndrome or Thrombophlebitis migrans)
- Thrombosis (e.g., phlebothrombosis, splenic vein thrombosis)
- Impaired glucose tolerance (rarely)
- The symptoms of pancreatic cancer may be similar to those of chronic pancreatitis. Differential diagnosis is difficult since carcinoma may be accompanied by pancreatitis!
- No screening tests available
Tumor markers: CA 19-9 and CEA
- Used to monitor the progression of cancer and treatment efficacy
- Possibly ↑ lipase
- First test: usually either contrast-enhanced abdominal CT or ultrasound → if ultrasound reveals a pancreatic mass → subsequent CT
- Endoscopic or magnetic retrograde cholangiopancreatography (ERCP/MRCP): to rule out choledocholithiasis and/or if biliary decompression is indicated; , e.g., in case of palliative treatment to alleviate jaundice
- Endoscopic ultrasound (EUS)
Fine needle aspiration
- Not routinely performed
- Can help differentiate pancreatic cancer from pancreatitis (e.g., chronic or autoimmune)
- Can be done via EUS (preferred) or percutaneously (US or CT-guided)
- Clarify before tumor conference
- Abdominal ultrasound
- CT abdomen
- Chest x-ray
- CT thorax
- Alternative approach: surgical exploration with laparotomy in tumors classified as potentially resectable
Pancreatic exocrine tumors (95%)
- Mostly ductal adenocarcinoma with altered ductal structures with uneven multilayered epithelium
- Less common: acinar adenocarcinoma (acinar cells produce digestive enzymes) and others
- Pancreatic endocrine tumors (neuroendocrine tumors/NET, < 5% of tumors)
R classification system of resected pancreatic tissue
- The guidelines request that the surgeon marks the resection margins in a way that the pathologist can correctly assess them.
- Analogous to rectal carcinoma the distance from the tumor cell to the surgical resection margin is defined ("circumferential resection margin")
- Metastasis (e.g., breast carcinoma, bronchial carcinoma)
- Pancreatic pseudocyst
Pancreatic cyst: Epithelium-lined cyst, filled with serous or mucous liquid, often associated with the rare von-Hippel-Lindau syndrome; can be benign, precancerous or cancerous.
- Clinical features: abdominal pain, back pain, jaundice, and in case of infection, fever and sepsis
- CT scan: cyst appears as a well-circumscribed hyperdense mass in comparison to the surrounding tissue. Pancreatic cancer, on the other hand, is hypodense.
- ERCP: cyst shows contrast-enhancement
- Asymptomatic cyst: no surgical treatment
- Symptomatic cyst: CT-guided, endoscopic, or surgical drainage
Intraductal papillary mucinous neoplasms (IPMNs)
- Brief description: most frequent pancreatic lesion (about 20–30%); commonly located in the head of the pancreas. Histologically, intraductal papillary proliferations present with atypical columnar epithelium and variable mucinous content.
- Classification: "main duct type" and "branch duct type"
- Clinical features: One-third of all patients are asymptomatic. If symptoms occur, they resemble those of chronic pancreatitis.
- Diagnostics: : Initially, cross‑sectional imaging is performed (MRI with Magnetic resonance cholangiopancreatography (MRCP) or abdominal CT). Ultrasound or CT-guided fine-needle aspiration may help to confirm a diagnosis (particularly in branch duct type) or to assess malignancy.
- Main duct type: surgical resection
- Branch duct type: Surgical resection is only performed when IPMN meets malignancy criteria.
- If necessary, watchful-waiting in small branch-duct type in multimorbid older patients with high operative risk
Serous cystic neoplasms (SCNs)
- Brief description: SCNs account for approx. 10–20% of all cystic lesions. They typically occur in elderly women and are most frequently located in the body or the tail of the pancreas. Malignant transformation is extremely rare.
- Treatment: surgical resection only if symptoms like passage disorder or pain occur, or if lesion is > 4 cm in size
Mucinous cystic neoplasms (MCNs)
- Brief description:MCNs account for approx. 10% of all cystic lesions and only occur in women. Their most common localization is the tail of the pancreas. Imaging in MCN patients shows multilobular space-occupying lesions with a thick cyst wall. MCN typically show ovarian-like stroma. There is a 30–50% risk of malignancy in this type of cystic neoplasm. Therefore, surgical resection is generally recommended.
Solid-pseudopapillary neoplasms (SPNs)
- Brief description: SPNs are rare and are only responsible for approx. 5% of cystic lesions. There is a slight tendency for malignancy and in 5% of all diagnosed SPNs liver metastasis is present. Surgical resection is the goal even if metastasis is present. If complete surgical resection is successful, the overall prognosis is good.
Lipomas of the pancreas (pancreatic lipomas)
- Brief description: Pancreatic lipomas are very rare benign lesions of the pancreas. MRI typically shows a tissue which is isointense to fat. Malignant transformation of pancreatic lipomas into pancreatic liposarcomas is even rarer than the pancreatic lipomas themselves. Specific treatment is not necessary unless the lipoma causes complications; e.g., compression of neighboring organs can lead to organ dysfunction, pain, and other symptoms, which may require treatment (e.g., surgical resection).
The differential diagnoses listed here are not exhaustive.
As the only curative treatment option for pancreatic cancer is surgical resection, patients with operable tumors; (∼ 20%) are always recommended for surgery. If surgical tumor resection is not possible or distant metastasis is present, a palliative approach is chosen.
- Curative versus palliative treatment
Criteria for resectability
- Infiltration of neighboring organs: R0 resection is still possible. Surgical resection should be considered if the operation technique allows it.
Infiltration of arteries: If the celiac artery is infiltrated, surgical resection of the pancreatic carcinoma should not be performed.
- According to the NCCN (National Comprehensive Cancer Network) Guidelines, surgical resection is contraindicated in the case of celiac artery encasement greater than 180 degrees.
- Infiltration of veins: R0 resection is still possible when the portal vein, splenic vein, and superior mesenteric vein are infiltrated by the tumor; the determining factor for surgery is the possibility of reconstruction and the technical limits to it.
Borderline resectable tumors (NCNN guidelines)
- Infiltration of the superior mesenteric artery or the portal vein - Imaging shows that the tumor reaches the vessels but doesn't narrow them by compressing the veins and arteries.
- Encasement of the superior mesenteric vein and/or the portal vein by the tumor, but neighboring vessels are not completely encased by it
- Short-segment occlusion or stenosis of a vein caused by a thrombus or tumor encasement if there is enough vessel material for reconstruction at the proximal and distal end of the occlusion
- Short-segment encasement or tumor reaches the gastroduodenal artery or the proper hepatic artery but the celiac artery is not encased by the tumor
- Celiac encasement less than half of its circumference
- If the responsible surgeon has doubts about the resectability or does not have enough surgical experience, a second opinion should be obtained from a pancreas specialist.
Pancreatic head carcinoma: ("Whipple procedure"; method of choice)
- Resection of pancreatic head, distal stomach, duodenum, gallbladder, and common bile duct
- Reconstruction by enteroenterostomy or Roux-en-Y anastomosis from jejunum, and biliodigestive anastomosis
- (Traverso-Longmire procedure): a modification of the Whipple procedure that preserves the gastric antrum, the pylorus and a small part of the duodenum (anastomosed to the jejunum) to provide a more physiologic stomach emptying
- Pancreatic body and tail carcinoma
Neoadjuvant or adjuvant chemoradiotherapy
- To reduce tumor size, improve symptoms, and prolong life
- Chemotherapy or radiation therapy without surgery cannot cure the patient.
Adjuvant treatment (4–8 weeks post-surgery): At the moment, there is no recommendation for radiochemotherapy outside of clinical trials. In every patient with a curative treatment approach, an adjuvant IV chemotherapy with gemcitabine or 5-FU/folinic acid should be administered over 6 months, unless contraindicated.
- Contraindications for adjuvant chemotherapy
- Impaired infusion capacity in lung function testing is a specific contraindication for gemcitabine.
- Gemcitabine shows less toxicity compared to 5-FU/folinic acid but overall survival rates are similar.
Palliative chemotherapy: indicated in patients with advanced or metastatic pancreatic cancer until tumor progression or toxicity is not accepted
- Gemcitabine as monotherapy is typically used as first-line therapy.
Gemcitabine and the tyrosine kinase inhibitor erlotinib in combination show better efficacy compared to monotherapy.
- If acneiform eruptions don't occur after 8 weeks of treatment, erlotinib should be withdrawn.
Patients with a good performance index: possibly more aggressive chemotherapy regimens.
- 5-FU/folinic acid, irinotecan, and oxaliplatin according to the FOLFIRINOX regimen are an option for patients with ECOG 0-1, bilirubin level of max. 1.5 fold of the normal range and until 75 years of age.
- Gemcitabine in combination with paclitaxel (nab-paclitaxel, abraxane®) is another option in patients with a good performance index.
- Second-line therapy
- Chemotherapy regimens
The significantly limited prognosis in pancreatic cancer patients should always be taken into consideration when thinking about palliative chemotherapy. If side-effects are remarkable and the patient's quality of life is significantly impaired, withdrawal from therapy should be openly discussed with the patient!
Analgesia according to the WHO step-by-step plan
- Early consultation with a pain therapist for optimizing the need of coanalgesics and adjuvants may be indicated.
- When administering opioids: consistent treatment of paralytic constipation caused by these drugs (e.g., with macrogol )
- Prescription of on-demand medication: especially for pain which sets in with food intake
- Psycho-oncological service: medicinal and interventional pain management may be complemented by psycho-oncological treatment. The benefits of this complementary treatment must be assessed on an individual basis.
- Radiotherapy: used in patients with symptomatic metastasis, especially to the brain and bones (rare)
- Celiac ganglion block (Celiac plexus block)
Cholestasis : ERCP with stent implantation
- Implantation of a wire mesh-like configured and self-unfolding metal stent in the common bile duct or in the affected area of the biliary tree. In patients with a life expectancy of less than 3 months, a plastic stent can be used.
- If the tumor progresses and infiltrates the implanted metal stent it can be ablated using argon plasma coagulation (APC)
- Percutaneous transhepatic bile duct drainage (PTCD)
- Indication: if endoscopic approaches fail or are not possible
- Technique: especially as a combinatorial procedure with gastroenterostomy (see “Gastroenterostomy” below) and usually additional choledochojejunostomy
In tumor-induced passage disorders of the gastrointestinal tract
- Drug treatment attempt
- Percutaneous Endoscopic Jejunostomy (PEJ) tube
- Gastroenterostomy: best supportive care in patients with gastric outlet stenosis. The stomach is anastomosed with the small intestine bypassing the duodenum.
- Technique: anastomosis of the stomach and the duodenum (jejunum; short-circuit surgery)
Percutaneous endoscopic gastrostomy (PEG) tube as a relief tube: indicated for severe palliative patients with chronic ileus and subileus that are inoperable
- Technique: a PEG tube with a great lumen (20 Fr.) is set up as an outflow tube
- Nutrition counseling
- Lymphogenic and hematogenous metastasis
- Gastric outlet stenosis
- Stenosis of the common bile duct (cholestasis)
- Other complications
We list the most important complications. The selection is not exhaustive.